Neurology

Pediatric headache and migraine are associated with a variety of conditions including respiratory, gastrointestinal, neurologic, and mood disorders, according to findings published in the Journal of Pediatrics.

Marta Ortiz/iStock/Getty Images Plus

In a study of 9,329 pediatric patients from the Philadelphia Neurodevelopmental Cohort, at the University of Pennsylvania, children with any headache type were more likely to have cardiovascular (odds ratio, 1.4; 95% confidence interval, 1.1-1.7) and gastrointestinal (OR, 1.2; 95% CI, 1.1-1.4) problems than did those without headache. In addition, they were more likely to have attention deficit hyperactivity disorder (OR, 1.2; 95% CI, 1.1-1.4), wrote Tarannum M. Lateef, MD, MPH, of the Center for Neuroscience and Behavioral Medicine at Children’s National Medical Center in Washington, and her coauthors.

Study participants were aged 8-21 years and were enrolled in the cohort from November 2009 to November 2011. Physical conditions were identified using EMRs and interviews and were later grouped together by general category.

Patients were asked about lifetime headache and migraine symptoms including sensitivity to light and noise, gastrointestinal symptoms, unilateral pain, throbbing and pulsation, and interference at school or work. Migraine was defined as headache accompanied by any three of these symptoms. Mental disorders were identified using an abbreviated version of the Kiddie-Schedule for Affective Disorders and Schizophrenia, reported Dr. Lateef and her associates.

Lifetime prevalence of any headache was 45.5%, and 22.6% for migraine. Migraine was more common in female patients (25.5%) than in male patients (19.4%).

Compared with nonmigraine headache patients, those with migraine more frequently had neurologic/central nervous system disorders (OR, 1.7; 95% CI, 1.4-2.0), developmental disorders (OR, 1.3; 95% CI, 1.1-1.6), respiratory problems (OR, 1.3; 95% CI, 1.1-1.6), anxiety (OR, 1.6; 95% CI, 1.3-2), mood disorders (OR, 2; 95% CI, 1.6-2.3), and behavioral disorders (OR, 1.3; 95% CI, 1.1-1.6).

The results suggest that “headache, particularly migraine, is associated with respiratory and other neurologic and developmental disorders, as well as with anxiety and mood disorders,” the authors wrote.

“Comorbidity may be an important index of heterogeneity … that can guide clinical management, genetic investigation, and future research on shared pathophysiology” with other disorders, they concluded.

No disclosures were reported.
 

SOURCE: Lateef T et al. J Pediatr. 2018 Oct 29. doi: 10.1016/j.jpeds.2018.09.033.

Pediatric headache and migraine are associated with a variety of conditions including respiratory, gastrointestinal, neurologic, and mood disorders, according to findings published in the Journal of Pediatrics.

Marta Ortiz/iStock/Getty Images Plus

In a study of 9,329 pediatric patients from the Philadelphia Neurodevelopmental Cohort, at the University of Pennsylvania, children with any headache type were more likely to have cardiovascular (odds ratio, 1.4; 95% confidence interval, 1.1-1.7) and gastrointestinal (OR, 1.2; 95% CI, 1.1-1.4) problems than did those without headache. In addition, they were more likely to have attention deficit hyperactivity disorder (OR, 1.2; 95% CI, 1.1-1.4), wrote Tarannum M. Lateef, MD, MPH, of the Center for Neuroscience and Behavioral Medicine at Children’s National Medical Center in Washington, and her coauthors.

Study participants were aged 8-21 years and were enrolled in the cohort from November 2009 to November 2011. Physical conditions were identified using EMRs and interviews and were later grouped together by general category.

Patients were asked about lifetime headache and migraine symptoms including sensitivity to light and noise, gastrointestinal symptoms, unilateral pain, throbbing and pulsation, and interference at school or work. Migraine was defined as headache accompanied by any three of these symptoms. Mental disorders were identified using an abbreviated version of the Kiddie-Schedule for Affective Disorders and Schizophrenia, reported Dr. Lateef and her associates.

Lifetime prevalence of any headache was 45.5%, and 22.6% for migraine. Migraine was more common in female patients (25.5%) than in male patients (19.4%).

Compared with nonmigraine headache patients, those with migraine more frequently had neurologic/central nervous system disorders (OR, 1.7; 95% CI, 1.4-2.0), developmental disorders (OR, 1.3; 95% CI, 1.1-1.6), respiratory problems (OR, 1.3; 95% CI, 1.1-1.6), anxiety (OR, 1.6; 95% CI, 1.3-2), mood disorders (OR, 2; 95% CI, 1.6-2.3), and behavioral disorders (OR, 1.3; 95% CI, 1.1-1.6).

The results suggest that “headache, particularly migraine, is associated with respiratory and other neurologic and developmental disorders, as well as with anxiety and mood disorders,” the authors wrote.

“Comorbidity may be an important index of heterogeneity … that can guide clinical management, genetic investigation, and future research on shared pathophysiology” with other disorders, they concluded.

No disclosures were reported.
 

SOURCE: Lateef T et al. J Pediatr. 2018 Oct 29. doi: 10.1016/j.jpeds.2018.09.033.

Pediatric headache and migraine are associated with a variety of conditions including respiratory, gastrointestinal, neurologic, and mood disorders, according to findings published in the Journal of Pediatrics.

Marta Ortiz/iStock/Getty Images Plus

In a study of 9,329 pediatric patients from the Philadelphia Neurodevelopmental Cohort, at the University of Pennsylvania, children with any headache type were more likely to have cardiovascular (odds ratio, 1.4; 95% confidence interval, 1.1-1.7) and gastrointestinal (OR, 1.2; 95% CI, 1.1-1.4) problems than did those without headache. In addition, they were more likely to have attention deficit hyperactivity disorder (OR, 1.2; 95% CI, 1.1-1.4), wrote Tarannum M. Lateef, MD, MPH, of the Center for Neuroscience and Behavioral Medicine at Children’s National Medical Center in Washington, and her coauthors.

Study participants were aged 8-21 years and were enrolled in the cohort from November 2009 to November 2011. Physical conditions were identified using EMRs and interviews and were later grouped together by general category.

Patients were asked about lifetime headache and migraine symptoms including sensitivity to light and noise, gastrointestinal symptoms, unilateral pain, throbbing and pulsation, and interference at school or work. Migraine was defined as headache accompanied by any three of these symptoms. Mental disorders were identified using an abbreviated version of the Kiddie-Schedule for Affective Disorders and Schizophrenia, reported Dr. Lateef and her associates.

Lifetime prevalence of any headache was 45.5%, and 22.6% for migraine. Migraine was more common in female patients (25.5%) than in male patients (19.4%).

Compared with nonmigraine headache patients, those with migraine more frequently had neurologic/central nervous system disorders (OR, 1.7; 95% CI, 1.4-2.0), developmental disorders (OR, 1.3; 95% CI, 1.1-1.6), respiratory problems (OR, 1.3; 95% CI, 1.1-1.6), anxiety (OR, 1.6; 95% CI, 1.3-2), mood disorders (OR, 2; 95% CI, 1.6-2.3), and behavioral disorders (OR, 1.3; 95% CI, 1.1-1.6).

The results suggest that “headache, particularly migraine, is associated with respiratory and other neurologic and developmental disorders, as well as with anxiety and mood disorders,” the authors wrote.

“Comorbidity may be an important index of heterogeneity … that can guide clinical management, genetic investigation, and future research on shared pathophysiology” with other disorders, they concluded.

No disclosures were reported.
 

SOURCE: Lateef T et al. J Pediatr. 2018 Oct 29. doi: 10.1016/j.jpeds.2018.09.033.

A series of three studies in college students showed that some serum markers are associated with concussion but the background level of the markers can vary considerably. There was no association between the markers and history of concussion, and they markers varied significantly by sex and race.

jpbcpa/Getty Images

The work, published in Neurology, suggests that there is hope for finding biomarkers for concussion, but much more work needs to be done.

Serum levels of amyloid beta 42 (Abeta42), total tau, and S100 calcium binding protein B (S100B) were associated with concussion, especially when tests were performed within 4 hours of the injury. However, the varying background levels indicate that these biomarkers are not yet ready for clinical application.

All three studies looked at serum levels of Abeta42, total tau, S100B, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), microtubule-associated protein 2 (MAP2), and 2’,3’-cyclic-nucleotide 3’-phosphodiesterase (CNPase).

In the first study, researchers recruited 415 college athletes without a concussion (61% male, 40% white). The researchers took measurements outside of the athletes’ competitive sports season to maximize the odds that the levels would represent a true baseline. The median time between blood draw and the last risk of head impact was 80 days (mean, 98.4 days; interquartile range, 38-204 days).

Males had higher levels of UCH-L1 (Cohen d = 0.75; P less than .001) and S100B (Cohen d = 0.56; P less than .001), while females had higher levels of CNPase (Cohen d = 0.43; P less than .001). White subjects had higher levels of Abeta42 (Cohen d = .28; P = .005) and CNPase (Cohen d = 0.46; P less than .001). Black subjects had higher levels of UCH-L1 (Cohen d = 0.61; P less than .001) and S100 B (Cohen d = 1.1; P less than .001).

The measurements were not particularly reliable, with retests over 6- to 12-month periods yielding varying results such that none of the test/retest cutoff points reached the cutoff for acceptable reliability.

The second study was an observational cohort study of the same 415 subjects. The researchers assessed the self-reported concussion history and the cumulative exposure to collision sports with serum levels of the above biomarkers. The only relationship between a biomarker history and self-reported concussions was higher baseline Abeta42, but that had a small effect size (P = .005). Among football players, there was no association between approximate number of head impacts and any baseline biomarker.

The third study looked at 31 subjects who had experienced a sports-related concussion, 29 of whom had had both a baseline and a postconcussion blood draw, and compared them with nonconcussed, demographically matched athletes.

Of all the biomarkers studied, only levels of S100B rose following a concussion, with 67% of concussed subjects experiencing such a change (P = .003). When the researchers restricted the analysis to subjects who had a blood draw within 4 hours of the concussion, 88% of the tests showed an increase (P = .001). UCH-L1 also rose in 86% of subjects, but this change was not significant after adjustment for multiple comparisons (P greater than .007).

Compared with controls, concussed individuals had significantly higher levels of Abeta42, total tau, S100B, and GFAP. Of the concussed patients, 79.4% had Abeta42 levels higher than the median of controls, 67.6% had higher levels of total tau than the median of controls, and 83.3% had higher levels of S100B. Restriction of analysis to blood drawn within 4 hours of the injury yielded values of 81.3%, 75.0%, and 88.2%, respectively.

When limited to blood draws taken within 4 hours of injury, the researchers found fair diagnostic accuracy for measurements of Abeta42 (area under the curve, 0.75; 95% confidence interval, 0.59-0.91), total tau (AUC, 0.74; 95% CI, 0.58-0.90), and S100B (AUC, 0.75; 95% CI, 0.64-0.85). Abeta42 concentrations higher than 13.7 pg/mL were 75.0% sensitive and 82.4% specific to a sports-related concussion. Total tau concentrations higher than 1.7 pg/mL detected sports-related concussions at 75.0% sensitivity and 66.3% specificity, with acceptable diagnostic accuracy for white subjects (AUC, 0.82, 95% CI, 0.72-0.93). Also for white participants, S100B concentrations higher than 53 pg/mL predicted sports-related concussions with 83.3% sensitivity and 74.6% specificity.

The researchers found no associations between biomarkers and performance on clinical tests or time away from sports.

SOURCE: BM Asken et al. Neurology. 2018. doi: 10.1212/WNL.0000000000006613.

A series of three studies in college students showed that some serum markers are associated with concussion but the background level of the markers can vary considerably. There was no association between the markers and history of concussion, and they markers varied significantly by sex and race.

jpbcpa/Getty Images

The work, published in Neurology, suggests that there is hope for finding biomarkers for concussion, but much more work needs to be done.

Serum levels of amyloid beta 42 (Abeta42), total tau, and S100 calcium binding protein B (S100B) were associated with concussion, especially when tests were performed within 4 hours of the injury. However, the varying background levels indicate that these biomarkers are not yet ready for clinical application.

All three studies looked at serum levels of Abeta42, total tau, S100B, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), microtubule-associated protein 2 (MAP2), and 2’,3’-cyclic-nucleotide 3’-phosphodiesterase (CNPase).

In the first study, researchers recruited 415 college athletes without a concussion (61% male, 40% white). The researchers took measurements outside of the athletes’ competitive sports season to maximize the odds that the levels would represent a true baseline. The median time between blood draw and the last risk of head impact was 80 days (mean, 98.4 days; interquartile range, 38-204 days).

Males had higher levels of UCH-L1 (Cohen d = 0.75; P less than .001) and S100B (Cohen d = 0.56; P less than .001), while females had higher levels of CNPase (Cohen d = 0.43; P less than .001). White subjects had higher levels of Abeta42 (Cohen d = .28; P = .005) and CNPase (Cohen d = 0.46; P less than .001). Black subjects had higher levels of UCH-L1 (Cohen d = 0.61; P less than .001) and S100 B (Cohen d = 1.1; P less than .001).

The measurements were not particularly reliable, with retests over 6- to 12-month periods yielding varying results such that none of the test/retest cutoff points reached the cutoff for acceptable reliability.

The second study was an observational cohort study of the same 415 subjects. The researchers assessed the self-reported concussion history and the cumulative exposure to collision sports with serum levels of the above biomarkers. The only relationship between a biomarker history and self-reported concussions was higher baseline Abeta42, but that had a small effect size (P = .005). Among football players, there was no association between approximate number of head impacts and any baseline biomarker.

The third study looked at 31 subjects who had experienced a sports-related concussion, 29 of whom had had both a baseline and a postconcussion blood draw, and compared them with nonconcussed, demographically matched athletes.

Of all the biomarkers studied, only levels of S100B rose following a concussion, with 67% of concussed subjects experiencing such a change (P = .003). When the researchers restricted the analysis to subjects who had a blood draw within 4 hours of the concussion, 88% of the tests showed an increase (P = .001). UCH-L1 also rose in 86% of subjects, but this change was not significant after adjustment for multiple comparisons (P greater than .007).

Compared with controls, concussed individuals had significantly higher levels of Abeta42, total tau, S100B, and GFAP. Of the concussed patients, 79.4% had Abeta42 levels higher than the median of controls, 67.6% had higher levels of total tau than the median of controls, and 83.3% had higher levels of S100B. Restriction of analysis to blood drawn within 4 hours of the injury yielded values of 81.3%, 75.0%, and 88.2%, respectively.

When limited to blood draws taken within 4 hours of injury, the researchers found fair diagnostic accuracy for measurements of Abeta42 (area under the curve, 0.75; 95% confidence interval, 0.59-0.91), total tau (AUC, 0.74; 95% CI, 0.58-0.90), and S100B (AUC, 0.75; 95% CI, 0.64-0.85). Abeta42 concentrations higher than 13.7 pg/mL were 75.0% sensitive and 82.4% specific to a sports-related concussion. Total tau concentrations higher than 1.7 pg/mL detected sports-related concussions at 75.0% sensitivity and 66.3% specificity, with acceptable diagnostic accuracy for white subjects (AUC, 0.82, 95% CI, 0.72-0.93). Also for white participants, S100B concentrations higher than 53 pg/mL predicted sports-related concussions with 83.3% sensitivity and 74.6% specificity.

The researchers found no associations between biomarkers and performance on clinical tests or time away from sports.

SOURCE: BM Asken et al. Neurology. 2018. doi: 10.1212/WNL.0000000000006613.

A series of three studies in college students showed that some serum markers are associated with concussion but the background level of the markers can vary considerably. There was no association between the markers and history of concussion, and they markers varied significantly by sex and race.

jpbcpa/Getty Images

The work, published in Neurology, suggests that there is hope for finding biomarkers for concussion, but much more work needs to be done.

Serum levels of amyloid beta 42 (Abeta42), total tau, and S100 calcium binding protein B (S100B) were associated with concussion, especially when tests were performed within 4 hours of the injury. However, the varying background levels indicate that these biomarkers are not yet ready for clinical application.

All three studies looked at serum levels of Abeta42, total tau, S100B, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), glial fibrillary acidic protein (GFAP), microtubule-associated protein 2 (MAP2), and 2’,3’-cyclic-nucleotide 3’-phosphodiesterase (CNPase).

In the first study, researchers recruited 415 college athletes without a concussion (61% male, 40% white). The researchers took measurements outside of the athletes’ competitive sports season to maximize the odds that the levels would represent a true baseline. The median time between blood draw and the last risk of head impact was 80 days (mean, 98.4 days; interquartile range, 38-204 days).

Males had higher levels of UCH-L1 (Cohen d = 0.75; P less than .001) and S100B (Cohen d = 0.56; P less than .001), while females had higher levels of CNPase (Cohen d = 0.43; P less than .001). White subjects had higher levels of Abeta42 (Cohen d = .28; P = .005) and CNPase (Cohen d = 0.46; P less than .001). Black subjects had higher levels of UCH-L1 (Cohen d = 0.61; P less than .001) and S100 B (Cohen d = 1.1; P less than .001).

The measurements were not particularly reliable, with retests over 6- to 12-month periods yielding varying results such that none of the test/retest cutoff points reached the cutoff for acceptable reliability.

The second study was an observational cohort study of the same 415 subjects. The researchers assessed the self-reported concussion history and the cumulative exposure to collision sports with serum levels of the above biomarkers. The only relationship between a biomarker history and self-reported concussions was higher baseline Abeta42, but that had a small effect size (P = .005). Among football players, there was no association between approximate number of head impacts and any baseline biomarker.

The third study looked at 31 subjects who had experienced a sports-related concussion, 29 of whom had had both a baseline and a postconcussion blood draw, and compared them with nonconcussed, demographically matched athletes.

Of all the biomarkers studied, only levels of S100B rose following a concussion, with 67% of concussed subjects experiencing such a change (P = .003). When the researchers restricted the analysis to subjects who had a blood draw within 4 hours of the concussion, 88% of the tests showed an increase (P = .001). UCH-L1 also rose in 86% of subjects, but this change was not significant after adjustment for multiple comparisons (P greater than .007).

Compared with controls, concussed individuals had significantly higher levels of Abeta42, total tau, S100B, and GFAP. Of the concussed patients, 79.4% had Abeta42 levels higher than the median of controls, 67.6% had higher levels of total tau than the median of controls, and 83.3% had higher levels of S100B. Restriction of analysis to blood drawn within 4 hours of the injury yielded values of 81.3%, 75.0%, and 88.2%, respectively.

When limited to blood draws taken within 4 hours of injury, the researchers found fair diagnostic accuracy for measurements of Abeta42 (area under the curve, 0.75; 95% confidence interval, 0.59-0.91), total tau (AUC, 0.74; 95% CI, 0.58-0.90), and S100B (AUC, 0.75; 95% CI, 0.64-0.85). Abeta42 concentrations higher than 13.7 pg/mL were 75.0% sensitive and 82.4% specific to a sports-related concussion. Total tau concentrations higher than 1.7 pg/mL detected sports-related concussions at 75.0% sensitivity and 66.3% specificity, with acceptable diagnostic accuracy for white subjects (AUC, 0.82, 95% CI, 0.72-0.93). Also for white participants, S100B concentrations higher than 53 pg/mL predicted sports-related concussions with 83.3% sensitivity and 74.6% specificity.

The researchers found no associations between biomarkers and performance on clinical tests or time away from sports.

SOURCE: BM Asken et al. Neurology. 2018. doi: 10.1212/WNL.0000000000006613.

ATLANTA – In the fall of 2013, world-famous actor and comedian Robin Williams began to suffer symptoms from a disease he would never know the name of: Lewy body dementia.

Doug Brunk/MDedge News

“With our medical team’s care, for the next 10 months we chased symptoms, but they were so elusive,” Mr. Williams’ widow, Susan Schneider Williams, said during a keynote address at the annual meeting of the American Neurological Association. “One hallmark of LBD is that symptoms appear and disappear randomly. The game whack-a-mole comes to mind. As soon as you think you are about to figure out a symptom, it disappears, and another one pops up.”

Mr. Williams’ medical team included one general physician, one neurologist, one motor specialist, two psychiatrists, one hypnotherapist, one physical trainer, and assorted alternative specialists. “We had been celebrating our second wedding anniversary when Robin started having gut discomfort,” Ms. Williams recalled. “He was tested for diverticulitis [but] the results came back negative. The pain eventually subsided but what was alarming was Robin’s reaction to it. He had a sudden and sustained spike in fear and anxiety unlike anything I’d seen before. By that point, we’d been by each other’s side long enough that I knew his normal baseline moods, fears, and anxieties. This was totally out of character, and I wondered privately: ‘Is my husband a hypochondriac?’ What I know now is that he was exhibiting a notable hallmark of LBD: new onset anxiety, sustained.” Lewy body disease is characterized by more than 40 symptoms, she continued, “and Robin experienced nearly all of them. He was particularly debilitated by fear, anxiety, delusions, paranoia, and as I came to find out later, hallucinations.”

The medical team continued running all sorts of tests, but everything kept came back negative, except for a very high cortisol count. By the late spring of 2014, however, Mr. Williams was diagnosed with Parkinson’s disease. “I was relieved to find out we finally had an answer, but I could tell, Robin was not buying it,” said Ms. Williams, who is a California-based fine artist, author, and brain health advocate. “The motor specialist said it was early and mild and that he’d be feeling better once he adjusted to the medications, [that] he had another 10 good years.”

In an attempt to treat the Parkinson’s and what was assumed to be depression, his care plan involved adjusting Parkinson’s medications, combined with an antidepressant. His physician also recommended a visit to the Dan Anderson Renewal Center in Minnesota, “for enhanced 12-step work to augment his sobriety,” Ms. Williams said. “The hope was this might help with fear and anxiety. Robin was clean and sober for 8 continuous years when he passed. I watched how he gained spiritually in so many ways from all the work he’d been doing, but his brain biology was going in the exact opposite direction. He tried desperately to join the parts of his heart, mind, and spirit, but his brain was pulling him apart. I felt like I was watching my husband disintegrate before my eyes, and there was nothing anyone could do about it. There came a day when we were getting ready to go to one of our dear friend’s birthday party. I came and saw Robin as he lay on our bed, imprisoned by fear and anxiety. Through tears, he pleaded, ‘I just want to reboot my brain!’ I promised him, ‘I know, honey. I swear we’re going to get to the bottom of this.’ ”

The couple was about a week away from choosing which neurocognitive testing facility to go to for further evaluation when Mr. Williams took his own life in his Paradise Cay, Calif., home on Aug. 11, 2014. “Robin was exhausted from the terror coming from his brain,” Ms. Williams said. “He took [his own life] before it could take any more of him.”

[email protected]

ATLANTA – In the fall of 2013, world-famous actor and comedian Robin Williams began to suffer symptoms from a disease he would never know the name of: Lewy body dementia.

Doug Brunk/MDedge News

“With our medical team’s care, for the next 10 months we chased symptoms, but they were so elusive,” Mr. Williams’ widow, Susan Schneider Williams, said during a keynote address at the annual meeting of the American Neurological Association. “One hallmark of LBD is that symptoms appear and disappear randomly. The game whack-a-mole comes to mind. As soon as you think you are about to figure out a symptom, it disappears, and another one pops up.”

Mr. Williams’ medical team included one general physician, one neurologist, one motor specialist, two psychiatrists, one hypnotherapist, one physical trainer, and assorted alternative specialists. “We had been celebrating our second wedding anniversary when Robin started having gut discomfort,” Ms. Williams recalled. “He was tested for diverticulitis [but] the results came back negative. The pain eventually subsided but what was alarming was Robin’s reaction to it. He had a sudden and sustained spike in fear and anxiety unlike anything I’d seen before. By that point, we’d been by each other’s side long enough that I knew his normal baseline moods, fears, and anxieties. This was totally out of character, and I wondered privately: ‘Is my husband a hypochondriac?’ What I know now is that he was exhibiting a notable hallmark of LBD: new onset anxiety, sustained.” Lewy body disease is characterized by more than 40 symptoms, she continued, “and Robin experienced nearly all of them. He was particularly debilitated by fear, anxiety, delusions, paranoia, and as I came to find out later, hallucinations.”

The medical team continued running all sorts of tests, but everything kept came back negative, except for a very high cortisol count. By the late spring of 2014, however, Mr. Williams was diagnosed with Parkinson’s disease. “I was relieved to find out we finally had an answer, but I could tell, Robin was not buying it,” said Ms. Williams, who is a California-based fine artist, author, and brain health advocate. “The motor specialist said it was early and mild and that he’d be feeling better once he adjusted to the medications, [that] he had another 10 good years.”

In an attempt to treat the Parkinson’s and what was assumed to be depression, his care plan involved adjusting Parkinson’s medications, combined with an antidepressant. His physician also recommended a visit to the Dan Anderson Renewal Center in Minnesota, “for enhanced 12-step work to augment his sobriety,” Ms. Williams said. “The hope was this might help with fear and anxiety. Robin was clean and sober for 8 continuous years when he passed. I watched how he gained spiritually in so many ways from all the work he’d been doing, but his brain biology was going in the exact opposite direction. He tried desperately to join the parts of his heart, mind, and spirit, but his brain was pulling him apart. I felt like I was watching my husband disintegrate before my eyes, and there was nothing anyone could do about it. There came a day when we were getting ready to go to one of our dear friend’s birthday party. I came and saw Robin as he lay on our bed, imprisoned by fear and anxiety. Through tears, he pleaded, ‘I just want to reboot my brain!’ I promised him, ‘I know, honey. I swear we’re going to get to the bottom of this.’ ”

The couple was about a week away from choosing which neurocognitive testing facility to go to for further evaluation when Mr. Williams took his own life in his Paradise Cay, Calif., home on Aug. 11, 2014. “Robin was exhausted from the terror coming from his brain,” Ms. Williams said. “He took [his own life] before it could take any more of him.”

[email protected]

ATLANTA – In the fall of 2013, world-famous actor and comedian Robin Williams began to suffer symptoms from a disease he would never know the name of: Lewy body dementia.

Doug Brunk/MDedge News

“With our medical team’s care, for the next 10 months we chased symptoms, but they were so elusive,” Mr. Williams’ widow, Susan Schneider Williams, said during a keynote address at the annual meeting of the American Neurological Association. “One hallmark of LBD is that symptoms appear and disappear randomly. The game whack-a-mole comes to mind. As soon as you think you are about to figure out a symptom, it disappears, and another one pops up.”

Mr. Williams’ medical team included one general physician, one neurologist, one motor specialist, two psychiatrists, one hypnotherapist, one physical trainer, and assorted alternative specialists. “We had been celebrating our second wedding anniversary when Robin started having gut discomfort,” Ms. Williams recalled. “He was tested for diverticulitis [but] the results came back negative. The pain eventually subsided but what was alarming was Robin’s reaction to it. He had a sudden and sustained spike in fear and anxiety unlike anything I’d seen before. By that point, we’d been by each other’s side long enough that I knew his normal baseline moods, fears, and anxieties. This was totally out of character, and I wondered privately: ‘Is my husband a hypochondriac?’ What I know now is that he was exhibiting a notable hallmark of LBD: new onset anxiety, sustained.” Lewy body disease is characterized by more than 40 symptoms, she continued, “and Robin experienced nearly all of them. He was particularly debilitated by fear, anxiety, delusions, paranoia, and as I came to find out later, hallucinations.”

The medical team continued running all sorts of tests, but everything kept came back negative, except for a very high cortisol count. By the late spring of 2014, however, Mr. Williams was diagnosed with Parkinson’s disease. “I was relieved to find out we finally had an answer, but I could tell, Robin was not buying it,” said Ms. Williams, who is a California-based fine artist, author, and brain health advocate. “The motor specialist said it was early and mild and that he’d be feeling better once he adjusted to the medications, [that] he had another 10 good years.”

In an attempt to treat the Parkinson’s and what was assumed to be depression, his care plan involved adjusting Parkinson’s medications, combined with an antidepressant. His physician also recommended a visit to the Dan Anderson Renewal Center in Minnesota, “for enhanced 12-step work to augment his sobriety,” Ms. Williams said. “The hope was this might help with fear and anxiety. Robin was clean and sober for 8 continuous years when he passed. I watched how he gained spiritually in so many ways from all the work he’d been doing, but his brain biology was going in the exact opposite direction. He tried desperately to join the parts of his heart, mind, and spirit, but his brain was pulling him apart. I felt like I was watching my husband disintegrate before my eyes, and there was nothing anyone could do about it. There came a day when we were getting ready to go to one of our dear friend’s birthday party. I came and saw Robin as he lay on our bed, imprisoned by fear and anxiety. Through tears, he pleaded, ‘I just want to reboot my brain!’ I promised him, ‘I know, honey. I swear we’re going to get to the bottom of this.’ ”

The couple was about a week away from choosing which neurocognitive testing facility to go to for further evaluation when Mr. Williams took his own life in his Paradise Cay, Calif., home on Aug. 11, 2014. “Robin was exhausted from the terror coming from his brain,” Ms. Williams said. “He took [his own life] before it could take any more of him.”

[email protected]

SEATTLE – A novel extrasynaptic gamma-aminobutyric acid (GABA)–receptor agonist called OV-101 was safe and well-tolerated in adult and adolescent Angelman syndrome patients in a 12-week phase 2 trial. In a secondary analysis, the treatment appeared to improve sleep.

Jim Kling/MDedge News

Angelman syndrome is associated with a microdeletion on chromosome 15 encompassing the ubiquitin protein ligase E3a (UBE3A) gene. The resulting loss of expression of the UBE3A protein leads to increases in the uptake of GABA and reduces levels of extrasynaptic GABA. Patients with Angelman syndrome typically have motor dysfunction, often extreme: “These kids are very excitable, very active, and they have lots of trouble with sleep,” said Alex Kolevzon, MD, professor of psychiatry and pediatrics at the Icahn School of Medicine at Mount Sinai, in an interview.

Dr. Kolevzon presented the results at a poster session at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The study was conducted at 12 sites in the United States and 1 in Israel. Ovid Pharmaceuticals plans to apply to the Food and Drug Administration later this year for approval. There is no existing drug for Angelman syndrome, and the study provided good safety reassurance. “There were some side effects, but for the most part we considered them mild, and only four (out of 88 subjects) discontinued because of side effects,” said Dr. Kolevzon.

The researchers used actigraphy to gain a more objective measure of sleep in the study participants. They randomized 88 patients with Angelman syndrome (aged 13-49 years) to receive placebo in the morning and 15 mg of OV-101 at night, 10 mg OVID-101 in the morning and 15 mg OVID-101 at night, or placebo both in the morning and at night.

Pyrexia occurred in 24% of the group who received the active drug only at night, 3% of the group given the twice-daily dose, and 7% of the placebo group. Seizures occurred in 7% of the once-daily group and 10% of the twice-daily group; seizures were not noted in the placebo group.

The main efficacy outcome measure was the Clinical Global Impressions-9 (CGI-9) scale. The once-daily group had a significant benefit in the sleep domain at 12 weeks, compared with placebo (difference, –0.77; P = .0141), but the twice-daily group had only a trend toward improvement in sleep (difference, –0.45; P = .1407).

Both active therapy groups had significant improvement in CGI-9 measures after 12 weeks of treatment compared to placebo – the twice-daily group (P = .0206, Fisher’s Exact Test) and the once-daily group (P = .0006, mixed model repeated measures analysis).

The actigraphy analysis, conducted in the 45% of patients who could tolerate its use, found that, compared to placebo, the once-daily dosing group experienced an 25.7 minute improvement in latency to sleep onset (P = .0147), as well an approximately 50 minute reduction in sleep time during the day, and a 3.65% improvement in sleep efficiency.

OV-101 has the potential to treat other conditions as well. “Obviously there are a lot of neurodevelopmental disorders where you see dysregulation between the GABAergic and glutamergic systems. This is a drug that has a unique effect on the GABAergic system. It’s already being studied in Fragile X syndrome, where we see this same kind of dysregulation and excess excitation,” said Dr. Kolevzon.

Dr. Kolevzon is a consultant for several drug companies including Ovid Therapeutics.
 

SOURCE: AACAP 2018. New Research Poster 3.1.

SEATTLE – A novel extrasynaptic gamma-aminobutyric acid (GABA)–receptor agonist called OV-101 was safe and well-tolerated in adult and adolescent Angelman syndrome patients in a 12-week phase 2 trial. In a secondary analysis, the treatment appeared to improve sleep.

Jim Kling/MDedge News

Angelman syndrome is associated with a microdeletion on chromosome 15 encompassing the ubiquitin protein ligase E3a (UBE3A) gene. The resulting loss of expression of the UBE3A protein leads to increases in the uptake of GABA and reduces levels of extrasynaptic GABA. Patients with Angelman syndrome typically have motor dysfunction, often extreme: “These kids are very excitable, very active, and they have lots of trouble with sleep,” said Alex Kolevzon, MD, professor of psychiatry and pediatrics at the Icahn School of Medicine at Mount Sinai, in an interview.

Dr. Kolevzon presented the results at a poster session at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The study was conducted at 12 sites in the United States and 1 in Israel. Ovid Pharmaceuticals plans to apply to the Food and Drug Administration later this year for approval. There is no existing drug for Angelman syndrome, and the study provided good safety reassurance. “There were some side effects, but for the most part we considered them mild, and only four (out of 88 subjects) discontinued because of side effects,” said Dr. Kolevzon.

The researchers used actigraphy to gain a more objective measure of sleep in the study participants. They randomized 88 patients with Angelman syndrome (aged 13-49 years) to receive placebo in the morning and 15 mg of OV-101 at night, 10 mg OVID-101 in the morning and 15 mg OVID-101 at night, or placebo both in the morning and at night.

Pyrexia occurred in 24% of the group who received the active drug only at night, 3% of the group given the twice-daily dose, and 7% of the placebo group. Seizures occurred in 7% of the once-daily group and 10% of the twice-daily group; seizures were not noted in the placebo group.

The main efficacy outcome measure was the Clinical Global Impressions-9 (CGI-9) scale. The once-daily group had a significant benefit in the sleep domain at 12 weeks, compared with placebo (difference, –0.77; P = .0141), but the twice-daily group had only a trend toward improvement in sleep (difference, –0.45; P = .1407).

Both active therapy groups had significant improvement in CGI-9 measures after 12 weeks of treatment compared to placebo – the twice-daily group (P = .0206, Fisher’s Exact Test) and the once-daily group (P = .0006, mixed model repeated measures analysis).

The actigraphy analysis, conducted in the 45% of patients who could tolerate its use, found that, compared to placebo, the once-daily dosing group experienced an 25.7 minute improvement in latency to sleep onset (P = .0147), as well an approximately 50 minute reduction in sleep time during the day, and a 3.65% improvement in sleep efficiency.

OV-101 has the potential to treat other conditions as well. “Obviously there are a lot of neurodevelopmental disorders where you see dysregulation between the GABAergic and glutamergic systems. This is a drug that has a unique effect on the GABAergic system. It’s already being studied in Fragile X syndrome, where we see this same kind of dysregulation and excess excitation,” said Dr. Kolevzon.

Dr. Kolevzon is a consultant for several drug companies including Ovid Therapeutics.
 

SOURCE: AACAP 2018. New Research Poster 3.1.

SEATTLE – A novel extrasynaptic gamma-aminobutyric acid (GABA)–receptor agonist called OV-101 was safe and well-tolerated in adult and adolescent Angelman syndrome patients in a 12-week phase 2 trial. In a secondary analysis, the treatment appeared to improve sleep.

Jim Kling/MDedge News

Angelman syndrome is associated with a microdeletion on chromosome 15 encompassing the ubiquitin protein ligase E3a (UBE3A) gene. The resulting loss of expression of the UBE3A protein leads to increases in the uptake of GABA and reduces levels of extrasynaptic GABA. Patients with Angelman syndrome typically have motor dysfunction, often extreme: “These kids are very excitable, very active, and they have lots of trouble with sleep,” said Alex Kolevzon, MD, professor of psychiatry and pediatrics at the Icahn School of Medicine at Mount Sinai, in an interview.

Dr. Kolevzon presented the results at a poster session at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The study was conducted at 12 sites in the United States and 1 in Israel. Ovid Pharmaceuticals plans to apply to the Food and Drug Administration later this year for approval. There is no existing drug for Angelman syndrome, and the study provided good safety reassurance. “There were some side effects, but for the most part we considered them mild, and only four (out of 88 subjects) discontinued because of side effects,” said Dr. Kolevzon.

The researchers used actigraphy to gain a more objective measure of sleep in the study participants. They randomized 88 patients with Angelman syndrome (aged 13-49 years) to receive placebo in the morning and 15 mg of OV-101 at night, 10 mg OVID-101 in the morning and 15 mg OVID-101 at night, or placebo both in the morning and at night.

Pyrexia occurred in 24% of the group who received the active drug only at night, 3% of the group given the twice-daily dose, and 7% of the placebo group. Seizures occurred in 7% of the once-daily group and 10% of the twice-daily group; seizures were not noted in the placebo group.

The main efficacy outcome measure was the Clinical Global Impressions-9 (CGI-9) scale. The once-daily group had a significant benefit in the sleep domain at 12 weeks, compared with placebo (difference, –0.77; P = .0141), but the twice-daily group had only a trend toward improvement in sleep (difference, –0.45; P = .1407).

Both active therapy groups had significant improvement in CGI-9 measures after 12 weeks of treatment compared to placebo – the twice-daily group (P = .0206, Fisher’s Exact Test) and the once-daily group (P = .0006, mixed model repeated measures analysis).

The actigraphy analysis, conducted in the 45% of patients who could tolerate its use, found that, compared to placebo, the once-daily dosing group experienced an 25.7 minute improvement in latency to sleep onset (P = .0147), as well an approximately 50 minute reduction in sleep time during the day, and a 3.65% improvement in sleep efficiency.

OV-101 has the potential to treat other conditions as well. “Obviously there are a lot of neurodevelopmental disorders where you see dysregulation between the GABAergic and glutamergic systems. This is a drug that has a unique effect on the GABAergic system. It’s already being studied in Fragile X syndrome, where we see this same kind of dysregulation and excess excitation,” said Dr. Kolevzon.

Dr. Kolevzon is a consultant for several drug companies including Ovid Therapeutics.
 

SOURCE: AACAP 2018. New Research Poster 3.1.

The Food and Drug Administration has approved Sympazan (clobazam) oral film for adjunctive treatment of Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older, according to a release from its developer. Final approval came after the orphan drug designation period for the previously marketed formulation, Onfi, came to an end in October.

LGS is a severe form of epilepsy; it can present with multiple types of seizures, as well as intellectual disabilities. Patients with LGS can have difficulty swallowing tablets or large volumes of oral suspension – which was previously the only way clobazam was delivered – because of physical limitations or behavioral or compliance issues. According to the press release from Aquestive Therapeutics, the Sympazan oral film might be able to get around those difficulties and reduce care burdens, especially with patients who are resistant to or even combative about treatment.

The approval is based on multiple pharmacokinetic studies that altogether showed that the oral film is bioequivalent to clobazam tablets and has a similar safety profile.

In a phase 3 study of 238 patients with LGS, clobazam tablets were shown to reduce drop seizures (those that involved falls) by 41% at low doses and by 68% at high doses versus a reduction of 12% seen with placebo (P less than .05 for all doses vs. placebo).

There is a risk of profound sedation when clobazam is used alongside benzodiazepines; there is also a risk of sedation and somnolence if it is used concomitantly with alcohol or other CNS depressants. Other risks associated with clobazam include suicidal ideation and behavior, serious dermatologic reactions, and physical and psychological dependence. The most common adverse reactions included constipation, pyrexia, lethargy, and drooling.

Full prescribing information can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved Sympazan (clobazam) oral film for adjunctive treatment of Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older, according to a release from its developer. Final approval came after the orphan drug designation period for the previously marketed formulation, Onfi, came to an end in October.

LGS is a severe form of epilepsy; it can present with multiple types of seizures, as well as intellectual disabilities. Patients with LGS can have difficulty swallowing tablets or large volumes of oral suspension – which was previously the only way clobazam was delivered – because of physical limitations or behavioral or compliance issues. According to the press release from Aquestive Therapeutics, the Sympazan oral film might be able to get around those difficulties and reduce care burdens, especially with patients who are resistant to or even combative about treatment.

The approval is based on multiple pharmacokinetic studies that altogether showed that the oral film is bioequivalent to clobazam tablets and has a similar safety profile.

In a phase 3 study of 238 patients with LGS, clobazam tablets were shown to reduce drop seizures (those that involved falls) by 41% at low doses and by 68% at high doses versus a reduction of 12% seen with placebo (P less than .05 for all doses vs. placebo).

There is a risk of profound sedation when clobazam is used alongside benzodiazepines; there is also a risk of sedation and somnolence if it is used concomitantly with alcohol or other CNS depressants. Other risks associated with clobazam include suicidal ideation and behavior, serious dermatologic reactions, and physical and psychological dependence. The most common adverse reactions included constipation, pyrexia, lethargy, and drooling.

Full prescribing information can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved Sympazan (clobazam) oral film for adjunctive treatment of Lennox-Gastaut syndrome (LGS) in patients aged 2 years and older, according to a release from its developer. Final approval came after the orphan drug designation period for the previously marketed formulation, Onfi, came to an end in October.

LGS is a severe form of epilepsy; it can present with multiple types of seizures, as well as intellectual disabilities. Patients with LGS can have difficulty swallowing tablets or large volumes of oral suspension – which was previously the only way clobazam was delivered – because of physical limitations or behavioral or compliance issues. According to the press release from Aquestive Therapeutics, the Sympazan oral film might be able to get around those difficulties and reduce care burdens, especially with patients who are resistant to or even combative about treatment.

The approval is based on multiple pharmacokinetic studies that altogether showed that the oral film is bioequivalent to clobazam tablets and has a similar safety profile.

In a phase 3 study of 238 patients with LGS, clobazam tablets were shown to reduce drop seizures (those that involved falls) by 41% at low doses and by 68% at high doses versus a reduction of 12% seen with placebo (P less than .05 for all doses vs. placebo).

There is a risk of profound sedation when clobazam is used alongside benzodiazepines; there is also a risk of sedation and somnolence if it is used concomitantly with alcohol or other CNS depressants. Other risks associated with clobazam include suicidal ideation and behavior, serious dermatologic reactions, and physical and psychological dependence. The most common adverse reactions included constipation, pyrexia, lethargy, and drooling.

Full prescribing information can be found on the FDA website.

[email protected]

The timing of the Food and Drug Administration’s Nov. 2 approval of the medication Dsuvia, a sublingual formulation of the synthetic opioid sufentanil, is interesting – to say the least. Dsuvia is a powerful pain medication, said to be 10 times more potent than fentanyl and 1,000 times more potent than morphine. The medication, developed by AcelRx Pharmaceuticals for use in medically supervised settings, has an indication for moderate to severe pain, and is packaged in single-dose applicators.

The chairperson of the FDA’s Anesthetic and Analgesics Drug Product Advisory Committee, Raeford E. Brown Jr., MD, a professor of pediatric anesthesia at the University of Kentucky, Lexington, could not be present Oct. 12 at the committee vote recommending approval. With the consumer advocacy group Public Citizen, Dr. Brown wrote a letter to FDA leaders detailing concerns about the new formulation of sufentanil.

“It is my observation,” Dr. Brown wrote, “that once the FDA approves an opioid compound, there are no safeguards as to the population that will be exposed, the postmarketing analysis of prescribing behavior, or the ongoing analysis of the risks of the drug to the general population relative to its benefit to the public health. Briefly stated, for all of the opioids that have been marketed in the last 10 years, there has not been sufficient demonstration of safety, nor has there been postmarketing assessment of who is taking the drug, how often prescribing is inappropriate, and whether there was ever a reason to risk the health of the general population by having one more opioid on the market.”

Dr. Brown went on to detail his concerns about sufentanil. In the intravenous formulation, the medication has been in use for more than two decades.

“It is so potent that abusers of this intravenous formulation often die when they inject the first dose; I have witnessed this in resuscitating physicians, medical students, technicians, and other health care providers, some successfully, as a part of my duties as a clinician in a major academic medical center. Because it is so potent, the dosing volume, whether in the IV formulation or the sublingual form, can be quite small. It is thus an extremely divertible drug, and I predict that we will encounter diversion, abuse, and death within the early months of its availability on the market.”

The letter finishes by criticizing the fact that the full Drug Safety and Risk Management Advisory Committee was not invited to the Oct. 12 meeting, and finally, about the ease of diversion among health care professionals – and anesthesiologists in particular.

Meanwhile, Scott Gottlieb, MD, commissioner of the FDA, posted a lengthy explanation on the organization’s website on Nov. 2, after the vote. In his statement on the agency’s approval of Dsuvia and the FDA’s future consideration of new opioids, Dr. Gottlieb explains: “To address concerns about the potential risks associated with Dsuvia, this product will have strong limitations on its use. It can’t be dispensed to patients for home use and should not be used for more than 72 hours. And it should only be administered by a health care provider using a single-dose applicator. That means it won’t be available at retail pharmacies for patients to take home. These measures to restrict the use of this product only within a supervised health care setting, and not for home use, are important steps to help prevent misuse and abuse of Dsuvia, as well reduce the potential for diversion. Because of the risks of addiction, abuse, and misuse with opioids, Dsuvia also is to be reserved for use in patients for whom alternative pain treatment options have not been tolerated, or are not expected to be tolerated, where existing treatment options have not provided adequate analgesia, or where these alternatives are not expected to provide adequate analgesia.”

In addition to the statement posted on the FDA’s website, Dr. Gottlieb made the approval of Dsuvia the topic of his weekly #SundayTweetorial on Nov. 4. In this venue, Dr. Gottlieb posts tweets on a single topic. On both Twitter and the FDA website, he noted that a major factor in the approval of Dsuvia was advantages it might convey for pain control to soldiers on the battlefield, where oral medications might take time to work and intravenous access might not be possible.

One tweet read: “Whether there’s a need for another powerful opioid in the throes of a massive crisis of addiction is a critical question. As a public health agency, we have an obligation to address this question for patients with pain, for the addiction crisis, for innovators, for all Americans.”

Another tweet stated, “While Dsuvia brings another highly potent opioid to market it fulfills a limited, unmet medical need in treating our nation’s soldiers on the battlefield. That’s why the Pentagon worked closely with the sponsor on developing Dsuvia. FDA committed to prioritize needs of our troops.”

Given our national overdose crisis, and issues of addiction with our soldiers and veterans, one has to wonder if the improvements afforded in pain control by Dsuvia will be worth the trade-off in possible deaths from misdirected use of a very potent agent. And while the new opioid may have been geared toward unmet military needs, Dsuvia will be available for use in civilian medical facilities as well.

There is some irony to the idea that a pharmaceutical company would continue to develop opioids when there is so much need for nonaddictive agents for pain control and so much pressure on physicians to limit access of opiates to pain patients. We are left to stand by and watch as yet another potent opioid preparation is introduced.
 

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016), and assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore.

The timing of the Food and Drug Administration’s Nov. 2 approval of the medication Dsuvia, a sublingual formulation of the synthetic opioid sufentanil, is interesting – to say the least. Dsuvia is a powerful pain medication, said to be 10 times more potent than fentanyl and 1,000 times more potent than morphine. The medication, developed by AcelRx Pharmaceuticals for use in medically supervised settings, has an indication for moderate to severe pain, and is packaged in single-dose applicators.

The chairperson of the FDA’s Anesthetic and Analgesics Drug Product Advisory Committee, Raeford E. Brown Jr., MD, a professor of pediatric anesthesia at the University of Kentucky, Lexington, could not be present Oct. 12 at the committee vote recommending approval. With the consumer advocacy group Public Citizen, Dr. Brown wrote a letter to FDA leaders detailing concerns about the new formulation of sufentanil.

“It is my observation,” Dr. Brown wrote, “that once the FDA approves an opioid compound, there are no safeguards as to the population that will be exposed, the postmarketing analysis of prescribing behavior, or the ongoing analysis of the risks of the drug to the general population relative to its benefit to the public health. Briefly stated, for all of the opioids that have been marketed in the last 10 years, there has not been sufficient demonstration of safety, nor has there been postmarketing assessment of who is taking the drug, how often prescribing is inappropriate, and whether there was ever a reason to risk the health of the general population by having one more opioid on the market.”

Dr. Brown went on to detail his concerns about sufentanil. In the intravenous formulation, the medication has been in use for more than two decades.

“It is so potent that abusers of this intravenous formulation often die when they inject the first dose; I have witnessed this in resuscitating physicians, medical students, technicians, and other health care providers, some successfully, as a part of my duties as a clinician in a major academic medical center. Because it is so potent, the dosing volume, whether in the IV formulation or the sublingual form, can be quite small. It is thus an extremely divertible drug, and I predict that we will encounter diversion, abuse, and death within the early months of its availability on the market.”

The letter finishes by criticizing the fact that the full Drug Safety and Risk Management Advisory Committee was not invited to the Oct. 12 meeting, and finally, about the ease of diversion among health care professionals – and anesthesiologists in particular.

Meanwhile, Scott Gottlieb, MD, commissioner of the FDA, posted a lengthy explanation on the organization’s website on Nov. 2, after the vote. In his statement on the agency’s approval of Dsuvia and the FDA’s future consideration of new opioids, Dr. Gottlieb explains: “To address concerns about the potential risks associated with Dsuvia, this product will have strong limitations on its use. It can’t be dispensed to patients for home use and should not be used for more than 72 hours. And it should only be administered by a health care provider using a single-dose applicator. That means it won’t be available at retail pharmacies for patients to take home. These measures to restrict the use of this product only within a supervised health care setting, and not for home use, are important steps to help prevent misuse and abuse of Dsuvia, as well reduce the potential for diversion. Because of the risks of addiction, abuse, and misuse with opioids, Dsuvia also is to be reserved for use in patients for whom alternative pain treatment options have not been tolerated, or are not expected to be tolerated, where existing treatment options have not provided adequate analgesia, or where these alternatives are not expected to provide adequate analgesia.”

In addition to the statement posted on the FDA’s website, Dr. Gottlieb made the approval of Dsuvia the topic of his weekly #SundayTweetorial on Nov. 4. In this venue, Dr. Gottlieb posts tweets on a single topic. On both Twitter and the FDA website, he noted that a major factor in the approval of Dsuvia was advantages it might convey for pain control to soldiers on the battlefield, where oral medications might take time to work and intravenous access might not be possible.

One tweet read: “Whether there’s a need for another powerful opioid in the throes of a massive crisis of addiction is a critical question. As a public health agency, we have an obligation to address this question for patients with pain, for the addiction crisis, for innovators, for all Americans.”

Another tweet stated, “While Dsuvia brings another highly potent opioid to market it fulfills a limited, unmet medical need in treating our nation’s soldiers on the battlefield. That’s why the Pentagon worked closely with the sponsor on developing Dsuvia. FDA committed to prioritize needs of our troops.”

Given our national overdose crisis, and issues of addiction with our soldiers and veterans, one has to wonder if the improvements afforded in pain control by Dsuvia will be worth the trade-off in possible deaths from misdirected use of a very potent agent. And while the new opioid may have been geared toward unmet military needs, Dsuvia will be available for use in civilian medical facilities as well.

There is some irony to the idea that a pharmaceutical company would continue to develop opioids when there is so much need for nonaddictive agents for pain control and so much pressure on physicians to limit access of opiates to pain patients. We are left to stand by and watch as yet another potent opioid preparation is introduced.
 

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016), and assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore.

The timing of the Food and Drug Administration’s Nov. 2 approval of the medication Dsuvia, a sublingual formulation of the synthetic opioid sufentanil, is interesting – to say the least. Dsuvia is a powerful pain medication, said to be 10 times more potent than fentanyl and 1,000 times more potent than morphine. The medication, developed by AcelRx Pharmaceuticals for use in medically supervised settings, has an indication for moderate to severe pain, and is packaged in single-dose applicators.

The chairperson of the FDA’s Anesthetic and Analgesics Drug Product Advisory Committee, Raeford E. Brown Jr., MD, a professor of pediatric anesthesia at the University of Kentucky, Lexington, could not be present Oct. 12 at the committee vote recommending approval. With the consumer advocacy group Public Citizen, Dr. Brown wrote a letter to FDA leaders detailing concerns about the new formulation of sufentanil.

“It is my observation,” Dr. Brown wrote, “that once the FDA approves an opioid compound, there are no safeguards as to the population that will be exposed, the postmarketing analysis of prescribing behavior, or the ongoing analysis of the risks of the drug to the general population relative to its benefit to the public health. Briefly stated, for all of the opioids that have been marketed in the last 10 years, there has not been sufficient demonstration of safety, nor has there been postmarketing assessment of who is taking the drug, how often prescribing is inappropriate, and whether there was ever a reason to risk the health of the general population by having one more opioid on the market.”

Dr. Brown went on to detail his concerns about sufentanil. In the intravenous formulation, the medication has been in use for more than two decades.

“It is so potent that abusers of this intravenous formulation often die when they inject the first dose; I have witnessed this in resuscitating physicians, medical students, technicians, and other health care providers, some successfully, as a part of my duties as a clinician in a major academic medical center. Because it is so potent, the dosing volume, whether in the IV formulation or the sublingual form, can be quite small. It is thus an extremely divertible drug, and I predict that we will encounter diversion, abuse, and death within the early months of its availability on the market.”

The letter finishes by criticizing the fact that the full Drug Safety and Risk Management Advisory Committee was not invited to the Oct. 12 meeting, and finally, about the ease of diversion among health care professionals – and anesthesiologists in particular.

Meanwhile, Scott Gottlieb, MD, commissioner of the FDA, posted a lengthy explanation on the organization’s website on Nov. 2, after the vote. In his statement on the agency’s approval of Dsuvia and the FDA’s future consideration of new opioids, Dr. Gottlieb explains: “To address concerns about the potential risks associated with Dsuvia, this product will have strong limitations on its use. It can’t be dispensed to patients for home use and should not be used for more than 72 hours. And it should only be administered by a health care provider using a single-dose applicator. That means it won’t be available at retail pharmacies for patients to take home. These measures to restrict the use of this product only within a supervised health care setting, and not for home use, are important steps to help prevent misuse and abuse of Dsuvia, as well reduce the potential for diversion. Because of the risks of addiction, abuse, and misuse with opioids, Dsuvia also is to be reserved for use in patients for whom alternative pain treatment options have not been tolerated, or are not expected to be tolerated, where existing treatment options have not provided adequate analgesia, or where these alternatives are not expected to provide adequate analgesia.”

In addition to the statement posted on the FDA’s website, Dr. Gottlieb made the approval of Dsuvia the topic of his weekly #SundayTweetorial on Nov. 4. In this venue, Dr. Gottlieb posts tweets on a single topic. On both Twitter and the FDA website, he noted that a major factor in the approval of Dsuvia was advantages it might convey for pain control to soldiers on the battlefield, where oral medications might take time to work and intravenous access might not be possible.

One tweet read: “Whether there’s a need for another powerful opioid in the throes of a massive crisis of addiction is a critical question. As a public health agency, we have an obligation to address this question for patients with pain, for the addiction crisis, for innovators, for all Americans.”

Another tweet stated, “While Dsuvia brings another highly potent opioid to market it fulfills a limited, unmet medical need in treating our nation’s soldiers on the battlefield. That’s why the Pentagon worked closely with the sponsor on developing Dsuvia. FDA committed to prioritize needs of our troops.”

Given our national overdose crisis, and issues of addiction with our soldiers and veterans, one has to wonder if the improvements afforded in pain control by Dsuvia will be worth the trade-off in possible deaths from misdirected use of a very potent agent. And while the new opioid may have been geared toward unmet military needs, Dsuvia will be available for use in civilian medical facilities as well.

There is some irony to the idea that a pharmaceutical company would continue to develop opioids when there is so much need for nonaddictive agents for pain control and so much pressure on physicians to limit access of opiates to pain patients. We are left to stand by and watch as yet another potent opioid preparation is introduced.
 

Dr. Miller is coauthor of “Committed: The Battle Over Involuntary Psychiatric Care” (Baltimore: Johns Hopkins University Press, 2016), and assistant professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore.

The Food and Drug Administration on Nov. 2 approved sufentanil (Dsuvia) for managing acute pain in adult patients in certified, medically supervised health care settings.

Sufentanil, an opioid analgesic manufactured by AcelRx Pharmaceuticals, was approved as a 30-mcg sublingual tablet. The efficacy of Dsuvia was shown in a randomized, clinical trial where patients who received the drug demonstrated significantly greater pain relief after both 15 minutes and 12 hours, compared with placebo.

“As a single-dose, noninvasive medication with a rapid reduction in pain intensity, Dsuvia represents an important alternative for health care providers to offer patients for acute pain management,” David Leiman, MD, of the department of surgery at the University of Texas, Houston, said in the AcelRx press statement.

FDA Commissioner Scott Gottlieb, MD, commented on the approval amid concerns expressed by some, such as the advocacy group Public Citizen, that the drug is “more than 1,000 times more potent than morphine,” and that approval could lead to diversion and abuse – particularly in light of the U.S. opioid epidemic.

In his statement, Dr. Gottlieb identified one broad, significant issue. “Why do we need an oral formulation of sufentanil – a more potent form of fentanyl that’s been approved for intravenous and epidural use in the U.S. since 1984 – on the market?”

In particular, he focused on the needs of the military. The Department of Defense has taken interest in sufentanil as it fulfills a small but specific battlefield need, namely as a means of pain relief in battlefield situations where soldiers cannot swallow oral medication and access to intravenous medication is limited.

Dr. Gottlieb made clear that sufentanil was meant only to be taken in controlled settings and will have strong limitations on its use. It cannot be prescribed for home use, and treatment should be limited to 72 hours. It can only be delivered by health care professionals using a single-dose applicator and will not be available in pharmacies. It is only to be used in patients who have not tolerated or are expected not to tolerate alternative methods of pain management.

“The FDA has implemented a REMS [Risk Evaluation and Mitigation Strategy] that reflects the potential risks associated with this product and mandates that Dsuvia will only be made available for use in a certified medically supervised heath care setting, including its use on the battlefield,” Dr. Gottlieb said.

However, he recognized that the debate runs deeper than how the FDA should mitigate risk over a new drug, and “as a public health agency, we have an obligation to address this question openly and directly. As a physician and regulator, I won’t bypass legitimate questions and concerns related to our role in addressing the opioid crisis,” he said.

Find Dr. Gottlieb’s full statement on the FDA website.

[email protected]

The Food and Drug Administration on Nov. 2 approved sufentanil (Dsuvia) for managing acute pain in adult patients in certified, medically supervised health care settings.

Sufentanil, an opioid analgesic manufactured by AcelRx Pharmaceuticals, was approved as a 30-mcg sublingual tablet. The efficacy of Dsuvia was shown in a randomized, clinical trial where patients who received the drug demonstrated significantly greater pain relief after both 15 minutes and 12 hours, compared with placebo.

“As a single-dose, noninvasive medication with a rapid reduction in pain intensity, Dsuvia represents an important alternative for health care providers to offer patients for acute pain management,” David Leiman, MD, of the department of surgery at the University of Texas, Houston, said in the AcelRx press statement.

FDA Commissioner Scott Gottlieb, MD, commented on the approval amid concerns expressed by some, such as the advocacy group Public Citizen, that the drug is “more than 1,000 times more potent than morphine,” and that approval could lead to diversion and abuse – particularly in light of the U.S. opioid epidemic.

In his statement, Dr. Gottlieb identified one broad, significant issue. “Why do we need an oral formulation of sufentanil – a more potent form of fentanyl that’s been approved for intravenous and epidural use in the U.S. since 1984 – on the market?”

In particular, he focused on the needs of the military. The Department of Defense has taken interest in sufentanil as it fulfills a small but specific battlefield need, namely as a means of pain relief in battlefield situations where soldiers cannot swallow oral medication and access to intravenous medication is limited.

Dr. Gottlieb made clear that sufentanil was meant only to be taken in controlled settings and will have strong limitations on its use. It cannot be prescribed for home use, and treatment should be limited to 72 hours. It can only be delivered by health care professionals using a single-dose applicator and will not be available in pharmacies. It is only to be used in patients who have not tolerated or are expected not to tolerate alternative methods of pain management.

“The FDA has implemented a REMS [Risk Evaluation and Mitigation Strategy] that reflects the potential risks associated with this product and mandates that Dsuvia will only be made available for use in a certified medically supervised heath care setting, including its use on the battlefield,” Dr. Gottlieb said.

However, he recognized that the debate runs deeper than how the FDA should mitigate risk over a new drug, and “as a public health agency, we have an obligation to address this question openly and directly. As a physician and regulator, I won’t bypass legitimate questions and concerns related to our role in addressing the opioid crisis,” he said.

Find Dr. Gottlieb’s full statement on the FDA website.

[email protected]

The Food and Drug Administration on Nov. 2 approved sufentanil (Dsuvia) for managing acute pain in adult patients in certified, medically supervised health care settings.

Sufentanil, an opioid analgesic manufactured by AcelRx Pharmaceuticals, was approved as a 30-mcg sublingual tablet. The efficacy of Dsuvia was shown in a randomized, clinical trial where patients who received the drug demonstrated significantly greater pain relief after both 15 minutes and 12 hours, compared with placebo.

“As a single-dose, noninvasive medication with a rapid reduction in pain intensity, Dsuvia represents an important alternative for health care providers to offer patients for acute pain management,” David Leiman, MD, of the department of surgery at the University of Texas, Houston, said in the AcelRx press statement.

FDA Commissioner Scott Gottlieb, MD, commented on the approval amid concerns expressed by some, such as the advocacy group Public Citizen, that the drug is “more than 1,000 times more potent than morphine,” and that approval could lead to diversion and abuse – particularly in light of the U.S. opioid epidemic.

In his statement, Dr. Gottlieb identified one broad, significant issue. “Why do we need an oral formulation of sufentanil – a more potent form of fentanyl that’s been approved for intravenous and epidural use in the U.S. since 1984 – on the market?”

In particular, he focused on the needs of the military. The Department of Defense has taken interest in sufentanil as it fulfills a small but specific battlefield need, namely as a means of pain relief in battlefield situations where soldiers cannot swallow oral medication and access to intravenous medication is limited.

Dr. Gottlieb made clear that sufentanil was meant only to be taken in controlled settings and will have strong limitations on its use. It cannot be prescribed for home use, and treatment should be limited to 72 hours. It can only be delivered by health care professionals using a single-dose applicator and will not be available in pharmacies. It is only to be used in patients who have not tolerated or are expected not to tolerate alternative methods of pain management.

“The FDA has implemented a REMS [Risk Evaluation and Mitigation Strategy] that reflects the potential risks associated with this product and mandates that Dsuvia will only be made available for use in a certified medically supervised heath care setting, including its use on the battlefield,” Dr. Gottlieb said.

However, he recognized that the debate runs deeper than how the FDA should mitigate risk over a new drug, and “as a public health agency, we have an obligation to address this question openly and directly. As a physician and regulator, I won’t bypass legitimate questions and concerns related to our role in addressing the opioid crisis,” he said.

Find Dr. Gottlieb’s full statement on the FDA website.

[email protected]

Appendectomy has been associated with a reduced risk of Parkinson’s disease (PD), which supports the potential for a reservoir of aggregated alpha-synuclein in the appendix to affect risk of the condition, according to new epidemiologic and translational evidence from two data sets that promotes a new and emerging theory for PD etiology.

decade3d/Thinkstock

When placed into the context of other recent studies, these epidemiologic data “point to the appendix as a site of origin for Parkinson’s and provide a path forward for devising new treatment strategies,” reported senior author Viviane Labrie, PhD, of the Van Andel Research Institute (VARI) in Grand Rapids, Mich.

The epidemiologic data was the most recent step in a series of findings summarized in a newly published paper in Science Translational Medicine. As the researchers explained, it is relevant to a separate body of evidence that alpha-synuclein, a protein that serves as the hallmark of PD when it appears in Lewy bodies, can be isolated in the nerve fibers and nerve cells of the appendix.

“We have shown that alpha-synuclein proteins, including the truncated forms observed in Lewy bodies, are abundant in the appendix,” reported first author Bryan A. Killinger, PhD, also at VARI, in a press teleconference. He said this finding is likely to explain the reduced risk of PD from appendectomy.

In the largest of the epidemiologic studies, the effect of appendectomy on subsequent risk of PD was evaluated through the health records from more than 1.6 million individuals in Sweden. The incidence of PD was found to be 19.3% lower among 551,647 patients who had an appendectomy, compared with controls.

In addition, the data showed that when PD did occur after appendectomy, it was delayed on average by 3.6 years. It is notable that appendectomy was not associated with protection from PD in patients with a familial link to PD, a group they said comprises less than 10% of cases.

In patients with PD, nonmotor symptoms often include GI tract dysfunction, which can, in some cases, be part of a prodromal presentation that precedes the onset of classical PD symptoms by several years, the authors reported. However, the new research upends previous conceptions of disease. The demonstration of abundant alpha-synuclein in the appendix coupled with the protective effect of appendectomy, suggests that PD may originate in the GI tract and then spread to the central nervous system (CNS) rather than the other way around.

“The vermiform appendix was once considered to be an unnecessary organ. Although there is now good evidence that the appendix plays a major role in the regulation of the immune system, including the regulation of gut bacteria, our work suggests it is also mediates risk of Parkinson’s,” Dr. Labrie said in the teleconference.

In the paper, numerous pieces of the puzzle are brought together to suggest that alpha-synuclein in the appendix is linked to alpha-synuclein in the CNS. Many of the findings along this investigative pathway were described as surprising. For example, immunohistochemistry studies revealed high amounts of alpha-synuclein in nearly every sample of appendiceal tissue examined, including normal and inflamed tissue, tissue from individuals with PD and those without, and tissues from young and old individuals.

B.A. Killinger et al., Science Translational Medicine (2018)

“The normal tissue, as well as appendiceal tissue from PD patients, contained high levels of alpha-synuclein in the truncated forms analogous to those seen in Lewy body pathology,” Dr. Killinger said. Based on these and other findings, he believes that alpha-synuclein in the appendix forms a reservoir for seeding the aggregates involved in the pathology of PD, although he acknowledged that it is not yet clear how the proteins in the appendix find their way to the brain.

From these data, it appears that most individuals with an intact appendix have alpha-synuclein in the nerve fibers, but Dr. Labrie pointed out that the only about 1% of the population develops PD. She speculated that there is “some confluence of events,” such as an environmental trigger altering the GI microbiome, that mediates ultimate risk of PD, but she noted that these events may take place decades before signs and symptoms of PD develop. The data appear to be a substantial reorientation in understanding PD.

“We have shown that the appendix is a hub for the accumulation of clumped forms of alpha-synuclein proteins, which are implicated in Parkinson’s,” Dr. Killinger said. “This knowledge will be invaluable as we explore new prevention and treatment strategies.”

The research was funded by a variety of governmental and private grants to individual authors. Dr. Killinger and Dr. Labrie report no financial relationships relevant to this study.

SOURCE: Killinger BA et al. Sci Transl Med. 2018;10:eaar5380.

Appendectomy has been associated with a reduced risk of Parkinson’s disease (PD), which supports the potential for a reservoir of aggregated alpha-synuclein in the appendix to affect risk of the condition, according to new epidemiologic and translational evidence from two data sets that promotes a new and emerging theory for PD etiology.

decade3d/Thinkstock

When placed into the context of other recent studies, these epidemiologic data “point to the appendix as a site of origin for Parkinson’s and provide a path forward for devising new treatment strategies,” reported senior author Viviane Labrie, PhD, of the Van Andel Research Institute (VARI) in Grand Rapids, Mich.

The epidemiologic data was the most recent step in a series of findings summarized in a newly published paper in Science Translational Medicine. As the researchers explained, it is relevant to a separate body of evidence that alpha-synuclein, a protein that serves as the hallmark of PD when it appears in Lewy bodies, can be isolated in the nerve fibers and nerve cells of the appendix.

“We have shown that alpha-synuclein proteins, including the truncated forms observed in Lewy bodies, are abundant in the appendix,” reported first author Bryan A. Killinger, PhD, also at VARI, in a press teleconference. He said this finding is likely to explain the reduced risk of PD from appendectomy.

In the largest of the epidemiologic studies, the effect of appendectomy on subsequent risk of PD was evaluated through the health records from more than 1.6 million individuals in Sweden. The incidence of PD was found to be 19.3% lower among 551,647 patients who had an appendectomy, compared with controls.

In addition, the data showed that when PD did occur after appendectomy, it was delayed on average by 3.6 years. It is notable that appendectomy was not associated with protection from PD in patients with a familial link to PD, a group they said comprises less than 10% of cases.

In patients with PD, nonmotor symptoms often include GI tract dysfunction, which can, in some cases, be part of a prodromal presentation that precedes the onset of classical PD symptoms by several years, the authors reported. However, the new research upends previous conceptions of disease. The demonstration of abundant alpha-synuclein in the appendix coupled with the protective effect of appendectomy, suggests that PD may originate in the GI tract and then spread to the central nervous system (CNS) rather than the other way around.

“The vermiform appendix was once considered to be an unnecessary organ. Although there is now good evidence that the appendix plays a major role in the regulation of the immune system, including the regulation of gut bacteria, our work suggests it is also mediates risk of Parkinson’s,” Dr. Labrie said in the teleconference.

In the paper, numerous pieces of the puzzle are brought together to suggest that alpha-synuclein in the appendix is linked to alpha-synuclein in the CNS. Many of the findings along this investigative pathway were described as surprising. For example, immunohistochemistry studies revealed high amounts of alpha-synuclein in nearly every sample of appendiceal tissue examined, including normal and inflamed tissue, tissue from individuals with PD and those without, and tissues from young and old individuals.

B.A. Killinger et al., Science Translational Medicine (2018)

“The normal tissue, as well as appendiceal tissue from PD patients, contained high levels of alpha-synuclein in the truncated forms analogous to those seen in Lewy body pathology,” Dr. Killinger said. Based on these and other findings, he believes that alpha-synuclein in the appendix forms a reservoir for seeding the aggregates involved in the pathology of PD, although he acknowledged that it is not yet clear how the proteins in the appendix find their way to the brain.

From these data, it appears that most individuals with an intact appendix have alpha-synuclein in the nerve fibers, but Dr. Labrie pointed out that the only about 1% of the population develops PD. She speculated that there is “some confluence of events,” such as an environmental trigger altering the GI microbiome, that mediates ultimate risk of PD, but she noted that these events may take place decades before signs and symptoms of PD develop. The data appear to be a substantial reorientation in understanding PD.

“We have shown that the appendix is a hub for the accumulation of clumped forms of alpha-synuclein proteins, which are implicated in Parkinson’s,” Dr. Killinger said. “This knowledge will be invaluable as we explore new prevention and treatment strategies.”

The research was funded by a variety of governmental and private grants to individual authors. Dr. Killinger and Dr. Labrie report no financial relationships relevant to this study.

SOURCE: Killinger BA et al. Sci Transl Med. 2018;10:eaar5380.

Appendectomy has been associated with a reduced risk of Parkinson’s disease (PD), which supports the potential for a reservoir of aggregated alpha-synuclein in the appendix to affect risk of the condition, according to new epidemiologic and translational evidence from two data sets that promotes a new and emerging theory for PD etiology.

decade3d/Thinkstock

When placed into the context of other recent studies, these epidemiologic data “point to the appendix as a site of origin for Parkinson’s and provide a path forward for devising new treatment strategies,” reported senior author Viviane Labrie, PhD, of the Van Andel Research Institute (VARI) in Grand Rapids, Mich.

The epidemiologic data was the most recent step in a series of findings summarized in a newly published paper in Science Translational Medicine. As the researchers explained, it is relevant to a separate body of evidence that alpha-synuclein, a protein that serves as the hallmark of PD when it appears in Lewy bodies, can be isolated in the nerve fibers and nerve cells of the appendix.

“We have shown that alpha-synuclein proteins, including the truncated forms observed in Lewy bodies, are abundant in the appendix,” reported first author Bryan A. Killinger, PhD, also at VARI, in a press teleconference. He said this finding is likely to explain the reduced risk of PD from appendectomy.

In the largest of the epidemiologic studies, the effect of appendectomy on subsequent risk of PD was evaluated through the health records from more than 1.6 million individuals in Sweden. The incidence of PD was found to be 19.3% lower among 551,647 patients who had an appendectomy, compared with controls.

In addition, the data showed that when PD did occur after appendectomy, it was delayed on average by 3.6 years. It is notable that appendectomy was not associated with protection from PD in patients with a familial link to PD, a group they said comprises less than 10% of cases.

In patients with PD, nonmotor symptoms often include GI tract dysfunction, which can, in some cases, be part of a prodromal presentation that precedes the onset of classical PD symptoms by several years, the authors reported. However, the new research upends previous conceptions of disease. The demonstration of abundant alpha-synuclein in the appendix coupled with the protective effect of appendectomy, suggests that PD may originate in the GI tract and then spread to the central nervous system (CNS) rather than the other way around.

“The vermiform appendix was once considered to be an unnecessary organ. Although there is now good evidence that the appendix plays a major role in the regulation of the immune system, including the regulation of gut bacteria, our work suggests it is also mediates risk of Parkinson’s,” Dr. Labrie said in the teleconference.

In the paper, numerous pieces of the puzzle are brought together to suggest that alpha-synuclein in the appendix is linked to alpha-synuclein in the CNS. Many of the findings along this investigative pathway were described as surprising. For example, immunohistochemistry studies revealed high amounts of alpha-synuclein in nearly every sample of appendiceal tissue examined, including normal and inflamed tissue, tissue from individuals with PD and those without, and tissues from young and old individuals.

B.A. Killinger et al., Science Translational Medicine (2018)

“The normal tissue, as well as appendiceal tissue from PD patients, contained high levels of alpha-synuclein in the truncated forms analogous to those seen in Lewy body pathology,” Dr. Killinger said. Based on these and other findings, he believes that alpha-synuclein in the appendix forms a reservoir for seeding the aggregates involved in the pathology of PD, although he acknowledged that it is not yet clear how the proteins in the appendix find their way to the brain.

From these data, it appears that most individuals with an intact appendix have alpha-synuclein in the nerve fibers, but Dr. Labrie pointed out that the only about 1% of the population develops PD. She speculated that there is “some confluence of events,” such as an environmental trigger altering the GI microbiome, that mediates ultimate risk of PD, but she noted that these events may take place decades before signs and symptoms of PD develop. The data appear to be a substantial reorientation in understanding PD.

“We have shown that the appendix is a hub for the accumulation of clumped forms of alpha-synuclein proteins, which are implicated in Parkinson’s,” Dr. Killinger said. “This knowledge will be invaluable as we explore new prevention and treatment strategies.”

The research was funded by a variety of governmental and private grants to individual authors. Dr. Killinger and Dr. Labrie report no financial relationships relevant to this study.

SOURCE: Killinger BA et al. Sci Transl Med. 2018;10:eaar5380.

The National Institutes of Health’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative will finish 2018 with its largest round of grant funding ever, giving $220 million to more than 200 research awards, and bringing this year’s total to more than $400 million, according to an announcement from the agency.

The BRAIN Initiative began in 2013 with the objective of revolutionizing our understanding of the human brain by accelerating the development and application of innovative technologies that will allow researchers to show how individual cells and complex neural circuits interact in both time and space and thereby seek new ways to treat, cure, and prevent brain disorders.

In the current round of funding that was authorized by Congress through the regular appropriations process and the 21st Century Cures Act, new projects include the creation of a wireless optical tomography cap for scanning human brain activity; the development of a noninvasive brain-computer interface system for improving the lives of paralysis patients; and the testing of noninvasive brain stimulation devices for treating schizophrenia, attention deficit disorders, and other brain diseases; the development of self-growing biological electrodes for recording brain activity; and the creation of an indestructible hydrogel system to help map neural circuits, according to the announcement.

Not all of the research involves technological advancement. In fact, one line of funding involves neuroethics. For instance, for epilepsy syndromes in the latest round of funding for 2018, researchers aim to explore ethical issues confronting families and clinicians when considering new treatment options for drug-resistant epilepsy in children.

The NIH is also leveraging some of the BRAIN Initiative funding toward finding new, nonaddictive pain treatments as part of the its HEAL (Helping to End Addiction Long-term) Initiative, such as support for research on the fundamental neurobiology of endogenous opioid systems.

[email protected]

The National Institutes of Health’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative will finish 2018 with its largest round of grant funding ever, giving $220 million to more than 200 research awards, and bringing this year’s total to more than $400 million, according to an announcement from the agency.

The BRAIN Initiative began in 2013 with the objective of revolutionizing our understanding of the human brain by accelerating the development and application of innovative technologies that will allow researchers to show how individual cells and complex neural circuits interact in both time and space and thereby seek new ways to treat, cure, and prevent brain disorders.

In the current round of funding that was authorized by Congress through the regular appropriations process and the 21st Century Cures Act, new projects include the creation of a wireless optical tomography cap for scanning human brain activity; the development of a noninvasive brain-computer interface system for improving the lives of paralysis patients; and the testing of noninvasive brain stimulation devices for treating schizophrenia, attention deficit disorders, and other brain diseases; the development of self-growing biological electrodes for recording brain activity; and the creation of an indestructible hydrogel system to help map neural circuits, according to the announcement.

Not all of the research involves technological advancement. In fact, one line of funding involves neuroethics. For instance, for epilepsy syndromes in the latest round of funding for 2018, researchers aim to explore ethical issues confronting families and clinicians when considering new treatment options for drug-resistant epilepsy in children.

The NIH is also leveraging some of the BRAIN Initiative funding toward finding new, nonaddictive pain treatments as part of the its HEAL (Helping to End Addiction Long-term) Initiative, such as support for research on the fundamental neurobiology of endogenous opioid systems.

[email protected]

The National Institutes of Health’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative will finish 2018 with its largest round of grant funding ever, giving $220 million to more than 200 research awards, and bringing this year’s total to more than $400 million, according to an announcement from the agency.

The BRAIN Initiative began in 2013 with the objective of revolutionizing our understanding of the human brain by accelerating the development and application of innovative technologies that will allow researchers to show how individual cells and complex neural circuits interact in both time and space and thereby seek new ways to treat, cure, and prevent brain disorders.

In the current round of funding that was authorized by Congress through the regular appropriations process and the 21st Century Cures Act, new projects include the creation of a wireless optical tomography cap for scanning human brain activity; the development of a noninvasive brain-computer interface system for improving the lives of paralysis patients; and the testing of noninvasive brain stimulation devices for treating schizophrenia, attention deficit disorders, and other brain diseases; the development of self-growing biological electrodes for recording brain activity; and the creation of an indestructible hydrogel system to help map neural circuits, according to the announcement.

Not all of the research involves technological advancement. In fact, one line of funding involves neuroethics. For instance, for epilepsy syndromes in the latest round of funding for 2018, researchers aim to explore ethical issues confronting families and clinicians when considering new treatment options for drug-resistant epilepsy in children.

The NIH is also leveraging some of the BRAIN Initiative funding toward finding new, nonaddictive pain treatments as part of the its HEAL (Helping to End Addiction Long-term) Initiative, such as support for research on the fundamental neurobiology of endogenous opioid systems.

[email protected]

MONTREAL – An extended time window for thrombolytic treatment of acute ischemic stroke patients using tissue plasminogen activator out to 9 hours from stroke onset was safe and effective using CT perfusion imaging and automated imaging processing software to select suitable patients in the EXTEND trial. This result matches the groundbreaking finding reported earlier in 2018 that used MRI to select patients for extended thrombolysis.

“To reproduce our results you need to set up CT perfusion” as well as the RAPID software for automated image processing to identify patients with a small infarct core and a large area of salvageable brain, said Henry Ma, MD, a stroke neurologist at Monash University, Melbourne, as he reported results from the trial at the World Stroke Congress. “EXTEND is the first positive thrombolysis trial in an extended time window using automated penumbral imaging.”

The new finding, from a trial with 225 randomized stroke patients, was especially notable because, by showing the validity of CT imaging for patient selection, it makes applying the extended time window for thrombolytic therapy more feasible for U.S. and Canadian stroke centers where CT imaging is much more common than MRI. A report from European investigators published in August 2018 from the WAKE-UP trial showed that thrombolysis with tissue plasminogen activator (tPA) was safe and effective when administered to patients who woke up with an acute ischemic stroke that had occurred more than 4.5 hours before treatment, but this study exclusively used MRI for patient selection (N Engl J Med. 2018 Aug 16;379[7]:611-22).

“In North America, our systems are more equipped for using CT,” commented Ashfaq Shuaib, MD, a professor of medicine and neurologist at the University of Alberta, Edmonton. Based on the WAKE-UP results, “MR would be preferred, but what we’ve been doing [since the WAKE-UP report] is if we see a CT scan that’s good we go ahead” with thrombolysis.

“Biologically, it doesn’t matter whether you use MR or CT; they both index the same underlying pathology. We’ve been hesitant to go beyond the MR finding from WAKE-UP, where there were data, but the findings from EXTEND were right in line with the WAKE-UP results, and that’s all we need to be reassured” that CT perfusion imaging also works for patient selection, commented Jeffrey L. Saver, MD, professor of medicine and director of the Comprehensive Stroke Center at the University of California, Los Angeles.

CT perfusion imaging and automated image processing “worked to select stroke patients” for an extended time window for treatment with mechanical thrombectomy in the DAWN (N Engl J Med. 2018 Jan 4;378[1]:11-21) and DEFUSE 3 (N Engl J Med. 2018 Feb 22;378[8]:308-18) trials, a history that makes the new finding of successfully using CT imaging to select patients who qualify for extended use of thrombolysis “a convincing result,” Dr. Saver said in an interview. The new EXTEND findings “will have a major impact” on using an extended time window for thrombolysis in U.S. practice, he predicted.

The EXTEND trial (Int J Stroke. 2012 Jan 1;7[1]:74-80) ran at 22 sites in Australia, 11 sites in Taiwan, and 1 center in New Zealand. Recruitment of patients into the study stopped early, after enrolling 225 patients, in June 2018, when results from WAKE-UP came out.

The EXTEND investigators enrolled patients who were either 4.5-9 hours out from the onset of their stroke or patients with a wake-up stroke with an uncertain onset. Participating centers could use either CT perfusion or MRI to identify candidates for treatment, and all used the RAPID software for image processing to identify patients with a perfusion lesion of at least 10 mL and an ischemic core volume no greater than 70 mL. Dr. Ma did not report what percentage of patients underwent imaging with each of these methods, but hinted that clinicians had used CT for a majority of the cases. The study randomized patients to receive either 0.9 mg/kg tPA or placebo, and by the trial protocol none of the enrolled patients received treatment with mechanical thrombectomy.

The trial’s primary endpoint was the percentage of patients with a modified Rankin Scale score of 0 or 1 at 90 days after their stroke, which was achieved by 44% more patients in the tPA group relative to the placebo arm after adjustment for age and baseline stroke severity, a statistically significant difference. The results were also positive for several secondary endpoints, such as recanalization 24 hours after treatment, which occurred in 67% of patients treated with tPA and 37% of the control patients, a statistically significant 68% relative improvement with thrombolysis.

Mortality at 90 days was similar in the two arms – 9% among the placebo patients and 12% among those who received tPA. The rate of symptomatic intracranial hemorrhage 36 hours after treatment was significantly higher among patients treated with tPA at 6%, compared with 1% in the placebo group, but the magnitude of this adverse effect was consistent with rates of intracranial hemorrhages previously reported in other studies of thrombolytic treatment for acute ischemic stroke, Dr. Ma said. The small number of increased intracranial hemorrhages “was not associated with increased mortality, and did not negate the positive result of an improved rate of excellent functional outcomes.”

These findings will likely spur further adoption of imaging processing software of the type used in EXTEND by U.S. stroke centers, Dr. Saver predicted.

“More and more centers have been getting this [software], and now they have two reasons to have it: to identify patients for an extended window for mechanical thrombectomy and to identify patients for an extended window for thrombolysis. It is a compelling case to have the imaging software as widely disseminated as possible. Centers that want to do the best for patients should have this imaging-processing software,” Dr. Saver said.

Dr. Ma and Dr. Shuaib reported no disclosures. Dr. Saver has received research funding and personal fees from Medtronic-Abbott and Neuravia.

[email protected]

SOURCE: Ma H et al. Int J. Stroke. 2018 Oct;13(2S):235, Abstract 1014.

MONTREAL – An extended time window for thrombolytic treatment of acute ischemic stroke patients using tissue plasminogen activator out to 9 hours from stroke onset was safe and effective using CT perfusion imaging and automated imaging processing software to select suitable patients in the EXTEND trial. This result matches the groundbreaking finding reported earlier in 2018 that used MRI to select patients for extended thrombolysis.

“To reproduce our results you need to set up CT perfusion” as well as the RAPID software for automated image processing to identify patients with a small infarct core and a large area of salvageable brain, said Henry Ma, MD, a stroke neurologist at Monash University, Melbourne, as he reported results from the trial at the World Stroke Congress. “EXTEND is the first positive thrombolysis trial in an extended time window using automated penumbral imaging.”

The new finding, from a trial with 225 randomized stroke patients, was especially notable because, by showing the validity of CT imaging for patient selection, it makes applying the extended time window for thrombolytic therapy more feasible for U.S. and Canadian stroke centers where CT imaging is much more common than MRI. A report from European investigators published in August 2018 from the WAKE-UP trial showed that thrombolysis with tissue plasminogen activator (tPA) was safe and effective when administered to patients who woke up with an acute ischemic stroke that had occurred more than 4.5 hours before treatment, but this study exclusively used MRI for patient selection (N Engl J Med. 2018 Aug 16;379[7]:611-22).

“In North America, our systems are more equipped for using CT,” commented Ashfaq Shuaib, MD, a professor of medicine and neurologist at the University of Alberta, Edmonton. Based on the WAKE-UP results, “MR would be preferred, but what we’ve been doing [since the WAKE-UP report] is if we see a CT scan that’s good we go ahead” with thrombolysis.

“Biologically, it doesn’t matter whether you use MR or CT; they both index the same underlying pathology. We’ve been hesitant to go beyond the MR finding from WAKE-UP, where there were data, but the findings from EXTEND were right in line with the WAKE-UP results, and that’s all we need to be reassured” that CT perfusion imaging also works for patient selection, commented Jeffrey L. Saver, MD, professor of medicine and director of the Comprehensive Stroke Center at the University of California, Los Angeles.

CT perfusion imaging and automated image processing “worked to select stroke patients” for an extended time window for treatment with mechanical thrombectomy in the DAWN (N Engl J Med. 2018 Jan 4;378[1]:11-21) and DEFUSE 3 (N Engl J Med. 2018 Feb 22;378[8]:308-18) trials, a history that makes the new finding of successfully using CT imaging to select patients who qualify for extended use of thrombolysis “a convincing result,” Dr. Saver said in an interview. The new EXTEND findings “will have a major impact” on using an extended time window for thrombolysis in U.S. practice, he predicted.

The EXTEND trial (Int J Stroke. 2012 Jan 1;7[1]:74-80) ran at 22 sites in Australia, 11 sites in Taiwan, and 1 center in New Zealand. Recruitment of patients into the study stopped early, after enrolling 225 patients, in June 2018, when results from WAKE-UP came out.

The EXTEND investigators enrolled patients who were either 4.5-9 hours out from the onset of their stroke or patients with a wake-up stroke with an uncertain onset. Participating centers could use either CT perfusion or MRI to identify candidates for treatment, and all used the RAPID software for image processing to identify patients with a perfusion lesion of at least 10 mL and an ischemic core volume no greater than 70 mL. Dr. Ma did not report what percentage of patients underwent imaging with each of these methods, but hinted that clinicians had used CT for a majority of the cases. The study randomized patients to receive either 0.9 mg/kg tPA or placebo, and by the trial protocol none of the enrolled patients received treatment with mechanical thrombectomy.

The trial’s primary endpoint was the percentage of patients with a modified Rankin Scale score of 0 or 1 at 90 days after their stroke, which was achieved by 44% more patients in the tPA group relative to the placebo arm after adjustment for age and baseline stroke severity, a statistically significant difference. The results were also positive for several secondary endpoints, such as recanalization 24 hours after treatment, which occurred in 67% of patients treated with tPA and 37% of the control patients, a statistically significant 68% relative improvement with thrombolysis.

Mortality at 90 days was similar in the two arms – 9% among the placebo patients and 12% among those who received tPA. The rate of symptomatic intracranial hemorrhage 36 hours after treatment was significantly higher among patients treated with tPA at 6%, compared with 1% in the placebo group, but the magnitude of this adverse effect was consistent with rates of intracranial hemorrhages previously reported in other studies of thrombolytic treatment for acute ischemic stroke, Dr. Ma said. The small number of increased intracranial hemorrhages “was not associated with increased mortality, and did not negate the positive result of an improved rate of excellent functional outcomes.”

These findings will likely spur further adoption of imaging processing software of the type used in EXTEND by U.S. stroke centers, Dr. Saver predicted.

“More and more centers have been getting this [software], and now they have two reasons to have it: to identify patients for an extended window for mechanical thrombectomy and to identify patients for an extended window for thrombolysis. It is a compelling case to have the imaging software as widely disseminated as possible. Centers that want to do the best for patients should have this imaging-processing software,” Dr. Saver said.

Dr. Ma and Dr. Shuaib reported no disclosures. Dr. Saver has received research funding and personal fees from Medtronic-Abbott and Neuravia.

[email protected]

SOURCE: Ma H et al. Int J. Stroke. 2018 Oct;13(2S):235, Abstract 1014.

MONTREAL – An extended time window for thrombolytic treatment of acute ischemic stroke patients using tissue plasminogen activator out to 9 hours from stroke onset was safe and effective using CT perfusion imaging and automated imaging processing software to select suitable patients in the EXTEND trial. This result matches the groundbreaking finding reported earlier in 2018 that used MRI to select patients for extended thrombolysis.

“To reproduce our results you need to set up CT perfusion” as well as the RAPID software for automated image processing to identify patients with a small infarct core and a large area of salvageable brain, said Henry Ma, MD, a stroke neurologist at Monash University, Melbourne, as he reported results from the trial at the World Stroke Congress. “EXTEND is the first positive thrombolysis trial in an extended time window using automated penumbral imaging.”

The new finding, from a trial with 225 randomized stroke patients, was especially notable because, by showing the validity of CT imaging for patient selection, it makes applying the extended time window for thrombolytic therapy more feasible for U.S. and Canadian stroke centers where CT imaging is much more common than MRI. A report from European investigators published in August 2018 from the WAKE-UP trial showed that thrombolysis with tissue plasminogen activator (tPA) was safe and effective when administered to patients who woke up with an acute ischemic stroke that had occurred more than 4.5 hours before treatment, but this study exclusively used MRI for patient selection (N Engl J Med. 2018 Aug 16;379[7]:611-22).

“In North America, our systems are more equipped for using CT,” commented Ashfaq Shuaib, MD, a professor of medicine and neurologist at the University of Alberta, Edmonton. Based on the WAKE-UP results, “MR would be preferred, but what we’ve been doing [since the WAKE-UP report] is if we see a CT scan that’s good we go ahead” with thrombolysis.

“Biologically, it doesn’t matter whether you use MR or CT; they both index the same underlying pathology. We’ve been hesitant to go beyond the MR finding from WAKE-UP, where there were data, but the findings from EXTEND were right in line with the WAKE-UP results, and that’s all we need to be reassured” that CT perfusion imaging also works for patient selection, commented Jeffrey L. Saver, MD, professor of medicine and director of the Comprehensive Stroke Center at the University of California, Los Angeles.

CT perfusion imaging and automated image processing “worked to select stroke patients” for an extended time window for treatment with mechanical thrombectomy in the DAWN (N Engl J Med. 2018 Jan 4;378[1]:11-21) and DEFUSE 3 (N Engl J Med. 2018 Feb 22;378[8]:308-18) trials, a history that makes the new finding of successfully using CT imaging to select patients who qualify for extended use of thrombolysis “a convincing result,” Dr. Saver said in an interview. The new EXTEND findings “will have a major impact” on using an extended time window for thrombolysis in U.S. practice, he predicted.

The EXTEND trial (Int J Stroke. 2012 Jan 1;7[1]:74-80) ran at 22 sites in Australia, 11 sites in Taiwan, and 1 center in New Zealand. Recruitment of patients into the study stopped early, after enrolling 225 patients, in June 2018, when results from WAKE-UP came out.

The EXTEND investigators enrolled patients who were either 4.5-9 hours out from the onset of their stroke or patients with a wake-up stroke with an uncertain onset. Participating centers could use either CT perfusion or MRI to identify candidates for treatment, and all used the RAPID software for image processing to identify patients with a perfusion lesion of at least 10 mL and an ischemic core volume no greater than 70 mL. Dr. Ma did not report what percentage of patients underwent imaging with each of these methods, but hinted that clinicians had used CT for a majority of the cases. The study randomized patients to receive either 0.9 mg/kg tPA or placebo, and by the trial protocol none of the enrolled patients received treatment with mechanical thrombectomy.

The trial’s primary endpoint was the percentage of patients with a modified Rankin Scale score of 0 or 1 at 90 days after their stroke, which was achieved by 44% more patients in the tPA group relative to the placebo arm after adjustment for age and baseline stroke severity, a statistically significant difference. The results were also positive for several secondary endpoints, such as recanalization 24 hours after treatment, which occurred in 67% of patients treated with tPA and 37% of the control patients, a statistically significant 68% relative improvement with thrombolysis.

Mortality at 90 days was similar in the two arms – 9% among the placebo patients and 12% among those who received tPA. The rate of symptomatic intracranial hemorrhage 36 hours after treatment was significantly higher among patients treated with tPA at 6%, compared with 1% in the placebo group, but the magnitude of this adverse effect was consistent with rates of intracranial hemorrhages previously reported in other studies of thrombolytic treatment for acute ischemic stroke, Dr. Ma said. The small number of increased intracranial hemorrhages “was not associated with increased mortality, and did not negate the positive result of an improved rate of excellent functional outcomes.”

These findings will likely spur further adoption of imaging processing software of the type used in EXTEND by U.S. stroke centers, Dr. Saver predicted.

“More and more centers have been getting this [software], and now they have two reasons to have it: to identify patients for an extended window for mechanical thrombectomy and to identify patients for an extended window for thrombolysis. It is a compelling case to have the imaging software as widely disseminated as possible. Centers that want to do the best for patients should have this imaging-processing software,” Dr. Saver said.

Dr. Ma and Dr. Shuaib reported no disclosures. Dr. Saver has received research funding and personal fees from Medtronic-Abbott and Neuravia.

[email protected]

SOURCE: Ma H et al. Int J. Stroke. 2018 Oct;13(2S):235, Abstract 1014.