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Lasmiditan is associated with driving impairment
Philadelphia – according to research presented at the annual meeting of the American Headache Society. This impairment coincides with the time of peak drug concentration and is resolved by 8 hours after dosing.
Lasmiditan, a 5-HT1F receptor agonist, is under regulatory review as an acute treatment of migraine in adults. In two phase 3 trials, a significant proportion of participants who received the treatment were pain-free at 2 hours and free of their most bothersome symptom at 2 hours, compared with controls. The most common treatment-emergent adverse events (dizziness, paresthesia, somnolence, fatigue, and hypoaesthesia) reflected the drug’s penetration of the CNS. Because CNS-related adverse events could affect a patient’s ability to drive, the effects of lasmiditan on simulated driving were studied, consistent with regulatory guidance.
Two studies in healthy participants
Eric Pearlman, MD, PhD, senior medical director for neuroscience, U.S. Medical Affairs, at Eli Lilly, and colleagues conducted two simulated driving studies with crossover designs. In the first study, the researchers randomized 90 healthy subjects (mean age, 34.9 years) to 50 mg, 100 mg, or 200 mg of lasmiditan; 1 mg of alprazolam (an active control); or placebo. After appropriate washout periods, participants received each treatment in random order. At 1.5 hours after each treatment, participants underwent a driving assessment using a driving simulator.
In the second study, Dr. Pearlman and colleagues randomized 68 healthy subjects (mean age, 32.8 years) to 100 mg or 200 mg of lasmiditan, 50 mg of diphenhydramine (an active control), or placebo. Participants underwent driving assessments at 8, 12, and 24 hours after baseline. Participants randomized to lasmiditan received treatment at baseline, but participants randomized to diphenhydramine received treatment 2 hours before each driving assessment. The diphenhydramine arm was intended to test the sensitivity of the driving assessment to impairment, as was the alprazolam arm in the first study.
During the driving assessments, participants were asked to maintain a speed of 100 km/h and to stay in the middle of the lane. The simulated road included gentle curves and hills, and oncoming traffic appeared occasionally. Participants also completed a secondary attention task, mimicking real-world conditions. Each assessment took about 1 hour. The primary endpoint was the standard deviation of lateral position (SDLP), which is known colloquially as weaving. The investigators defined noninferiority to placebo as an SDLP of 4.4 cm or less.
Participants reported that they could drive safely
In the first study, Dr. Pearlman and colleagues reported a dose-related increase in SDLP at 1.5 hours post treatment. All three doses of lasmiditan were inferior to placebo, in terms of their effect on SDLP. In the second study, both doses of lasmiditan were noninferior to placebo at 8 hours, 12 hours, and 24 hours. In both studies, the positive control confirmed the assay’s sensitivity to driving impairment. Secondary endpoints in the second study did not indicate an association between lasmiditan and clinically meaningful driving impairment at 8, 12, and 24 hours after dosing.
Single oral doses of lasmiditan were absorbed rapidly. The median time to peak concentration was approximately 2 hours, and the mean elimination half-life was about 4.25 hours. Exposure to lasmiditan was approximately dose proportional.
Before each driving assessment, investigators asked participants, “Do you feel safe to drive?” Depending on the dose, 55%-80% of participants responded affirmatively, but the majority of participants had clinically meaningful changes in SDLP. “This [result] is consistent with the FDA guidance in the literature that subject perception of safety to drive is faulty and supports the need for formal driving assessments,” said Dr. Pearlman.
Dizziness, somnolence, and headache were the most common adverse events in the study, and this result was similar to those of the phase 3 trials. Most of the adverse events were of mild to moderate severity.
Questions for further study
Among the questions that future research could address is whether the lasmiditan-related effects seen in these studies in healthy subjects are similar to those in patients with migraine when lasmiditan is taken to treat a migraine attack, said Dr. Pearlman. Another open question is whether migraine has ictal and interictal effects on driving performance.
Eli Lilly, which has developed lasmiditan, sponsored the studies. Dr. Pearlman and several of coinvestigators are employees of the company.
SOURCE: Pearlman E et al. AHS 2019, Abstract IOR06.
Philadelphia – according to research presented at the annual meeting of the American Headache Society. This impairment coincides with the time of peak drug concentration and is resolved by 8 hours after dosing.
Lasmiditan, a 5-HT1F receptor agonist, is under regulatory review as an acute treatment of migraine in adults. In two phase 3 trials, a significant proportion of participants who received the treatment were pain-free at 2 hours and free of their most bothersome symptom at 2 hours, compared with controls. The most common treatment-emergent adverse events (dizziness, paresthesia, somnolence, fatigue, and hypoaesthesia) reflected the drug’s penetration of the CNS. Because CNS-related adverse events could affect a patient’s ability to drive, the effects of lasmiditan on simulated driving were studied, consistent with regulatory guidance.
Two studies in healthy participants
Eric Pearlman, MD, PhD, senior medical director for neuroscience, U.S. Medical Affairs, at Eli Lilly, and colleagues conducted two simulated driving studies with crossover designs. In the first study, the researchers randomized 90 healthy subjects (mean age, 34.9 years) to 50 mg, 100 mg, or 200 mg of lasmiditan; 1 mg of alprazolam (an active control); or placebo. After appropriate washout periods, participants received each treatment in random order. At 1.5 hours after each treatment, participants underwent a driving assessment using a driving simulator.
In the second study, Dr. Pearlman and colleagues randomized 68 healthy subjects (mean age, 32.8 years) to 100 mg or 200 mg of lasmiditan, 50 mg of diphenhydramine (an active control), or placebo. Participants underwent driving assessments at 8, 12, and 24 hours after baseline. Participants randomized to lasmiditan received treatment at baseline, but participants randomized to diphenhydramine received treatment 2 hours before each driving assessment. The diphenhydramine arm was intended to test the sensitivity of the driving assessment to impairment, as was the alprazolam arm in the first study.
During the driving assessments, participants were asked to maintain a speed of 100 km/h and to stay in the middle of the lane. The simulated road included gentle curves and hills, and oncoming traffic appeared occasionally. Participants also completed a secondary attention task, mimicking real-world conditions. Each assessment took about 1 hour. The primary endpoint was the standard deviation of lateral position (SDLP), which is known colloquially as weaving. The investigators defined noninferiority to placebo as an SDLP of 4.4 cm or less.
Participants reported that they could drive safely
In the first study, Dr. Pearlman and colleagues reported a dose-related increase in SDLP at 1.5 hours post treatment. All three doses of lasmiditan were inferior to placebo, in terms of their effect on SDLP. In the second study, both doses of lasmiditan were noninferior to placebo at 8 hours, 12 hours, and 24 hours. In both studies, the positive control confirmed the assay’s sensitivity to driving impairment. Secondary endpoints in the second study did not indicate an association between lasmiditan and clinically meaningful driving impairment at 8, 12, and 24 hours after dosing.
Single oral doses of lasmiditan were absorbed rapidly. The median time to peak concentration was approximately 2 hours, and the mean elimination half-life was about 4.25 hours. Exposure to lasmiditan was approximately dose proportional.
Before each driving assessment, investigators asked participants, “Do you feel safe to drive?” Depending on the dose, 55%-80% of participants responded affirmatively, but the majority of participants had clinically meaningful changes in SDLP. “This [result] is consistent with the FDA guidance in the literature that subject perception of safety to drive is faulty and supports the need for formal driving assessments,” said Dr. Pearlman.
Dizziness, somnolence, and headache were the most common adverse events in the study, and this result was similar to those of the phase 3 trials. Most of the adverse events were of mild to moderate severity.
Questions for further study
Among the questions that future research could address is whether the lasmiditan-related effects seen in these studies in healthy subjects are similar to those in patients with migraine when lasmiditan is taken to treat a migraine attack, said Dr. Pearlman. Another open question is whether migraine has ictal and interictal effects on driving performance.
Eli Lilly, which has developed lasmiditan, sponsored the studies. Dr. Pearlman and several of coinvestigators are employees of the company.
SOURCE: Pearlman E et al. AHS 2019, Abstract IOR06.
Philadelphia – according to research presented at the annual meeting of the American Headache Society. This impairment coincides with the time of peak drug concentration and is resolved by 8 hours after dosing.
Lasmiditan, a 5-HT1F receptor agonist, is under regulatory review as an acute treatment of migraine in adults. In two phase 3 trials, a significant proportion of participants who received the treatment were pain-free at 2 hours and free of their most bothersome symptom at 2 hours, compared with controls. The most common treatment-emergent adverse events (dizziness, paresthesia, somnolence, fatigue, and hypoaesthesia) reflected the drug’s penetration of the CNS. Because CNS-related adverse events could affect a patient’s ability to drive, the effects of lasmiditan on simulated driving were studied, consistent with regulatory guidance.
Two studies in healthy participants
Eric Pearlman, MD, PhD, senior medical director for neuroscience, U.S. Medical Affairs, at Eli Lilly, and colleagues conducted two simulated driving studies with crossover designs. In the first study, the researchers randomized 90 healthy subjects (mean age, 34.9 years) to 50 mg, 100 mg, or 200 mg of lasmiditan; 1 mg of alprazolam (an active control); or placebo. After appropriate washout periods, participants received each treatment in random order. At 1.5 hours after each treatment, participants underwent a driving assessment using a driving simulator.
In the second study, Dr. Pearlman and colleagues randomized 68 healthy subjects (mean age, 32.8 years) to 100 mg or 200 mg of lasmiditan, 50 mg of diphenhydramine (an active control), or placebo. Participants underwent driving assessments at 8, 12, and 24 hours after baseline. Participants randomized to lasmiditan received treatment at baseline, but participants randomized to diphenhydramine received treatment 2 hours before each driving assessment. The diphenhydramine arm was intended to test the sensitivity of the driving assessment to impairment, as was the alprazolam arm in the first study.
During the driving assessments, participants were asked to maintain a speed of 100 km/h and to stay in the middle of the lane. The simulated road included gentle curves and hills, and oncoming traffic appeared occasionally. Participants also completed a secondary attention task, mimicking real-world conditions. Each assessment took about 1 hour. The primary endpoint was the standard deviation of lateral position (SDLP), which is known colloquially as weaving. The investigators defined noninferiority to placebo as an SDLP of 4.4 cm or less.
Participants reported that they could drive safely
In the first study, Dr. Pearlman and colleagues reported a dose-related increase in SDLP at 1.5 hours post treatment. All three doses of lasmiditan were inferior to placebo, in terms of their effect on SDLP. In the second study, both doses of lasmiditan were noninferior to placebo at 8 hours, 12 hours, and 24 hours. In both studies, the positive control confirmed the assay’s sensitivity to driving impairment. Secondary endpoints in the second study did not indicate an association between lasmiditan and clinically meaningful driving impairment at 8, 12, and 24 hours after dosing.
Single oral doses of lasmiditan were absorbed rapidly. The median time to peak concentration was approximately 2 hours, and the mean elimination half-life was about 4.25 hours. Exposure to lasmiditan was approximately dose proportional.
Before each driving assessment, investigators asked participants, “Do you feel safe to drive?” Depending on the dose, 55%-80% of participants responded affirmatively, but the majority of participants had clinically meaningful changes in SDLP. “This [result] is consistent with the FDA guidance in the literature that subject perception of safety to drive is faulty and supports the need for formal driving assessments,” said Dr. Pearlman.
Dizziness, somnolence, and headache were the most common adverse events in the study, and this result was similar to those of the phase 3 trials. Most of the adverse events were of mild to moderate severity.
Questions for further study
Among the questions that future research could address is whether the lasmiditan-related effects seen in these studies in healthy subjects are similar to those in patients with migraine when lasmiditan is taken to treat a migraine attack, said Dr. Pearlman. Another open question is whether migraine has ictal and interictal effects on driving performance.
Eli Lilly, which has developed lasmiditan, sponsored the studies. Dr. Pearlman and several of coinvestigators are employees of the company.
SOURCE: Pearlman E et al. AHS 2019, Abstract IOR06.
REPORTING FROM AHS 2019
Treatment of episodic cluster headache deviates from recommendations
PHILADELPHIA – , according to an analysis presented at the annual meeting of the American Headache Society.
Although consensus treatment guidelines do not exist for episodic cluster headache, treatment of this disorder did not follow many established recommendations that call for the use of preventive medications (e.g., MacGregor et al., 2010; Sarchielli et al., 2012; and May et al., 2006). Additional preventive medication options may be needed.
Patients with episodic cluster headache have several unilateral headache attacks per day. Little information is available to guide the selection of treatments for this population, and little is known about how available treatments are used in routine practice.
Analyzing cross-sectional survey data
To address this paucity of evidence, Jeffrey Scott Andrews, PharmD, a senior research scientist at Eli Lilly in Indianapolis, and colleagues examined data from the Adelphi 2017 Cluster Headache Disease Specific Programme, a large, international, cross-sectional survey. Physicians and patients in Germany, the United Kingdom, and the United States responded to the survey. Eligible physicians consulted with at least four patients with cluster headache per month, and eligible patients had a diagnosis of episodic cluster headache that was consistent with ICHD-3 beta criteria. Additional data were collected from all participants through questionnaires.
The analysis included 309 patients in Germany, 328 in the United Kingdom, and 375 in the United States. The average age of the patients was 40 years, and most of the patients were male. Less than 70% of patients reported working full time, which may indicate “the impact of this condition on work status,” said Dr. Andrews. Patients’ average number of attacks per day within an active period was 2.4. The two most commonly reported comorbidities were anxiety and depression. About 40% of cases of depression were reported to have occurred after the receipt of a diagnosis of cluster headache.
Use of inhaled oxygen was low
Most patients received acute treatments. The proportion of patients who received acute therapy only was 53% in Germany, 48% in the United Kingdom, and 43% in the United States. Approximately 34% of patients in Germany received a combination of acute and preventive therapy, compared with 37% in the United Kingdom and 42% in the United States. The proportion of patients who received preventive therapy only was 10% in Germany, 8% in the United Kingdom, and 12% in the United States.
The most commonly prescribed acute treatment, regardless of formulation, was sumatriptan. About 60% of patients received this medication. Less than one-third of patients used inhaled oxygen. Oxygen was prescribed more often in Germany (45%) and the United Kingdom (33%), compared with the United States (19%). U.S. patients face well-known obstacles in getting access to, and reimbursement for, oxygen, said Dr. Andrews. “That’s an area that deserves increased attention.” Zolmitriptan was the third most commonly prescribed acute medication.
Among prescriptions for sumatriptan, oral and injectable formulations were approximately equally common. Recommendations, however, indicate formulations with potentially fast onset of action. “The average duration of one of these attacks is between 15 and 180 minutes, so that certainly suggests that a formulation that gives you a faster onset of action might improve outcomes,” said Dr. Andrews. The use of injectable sumatriptan was lowest in the United States and highest in the United Kingdom.
“The most common decision regarding preventive treatment was [to give] no preventive treatment,” said Dr. Andrews. Verapamil was the most commonly prescribed preventive therapy (34% in Germany, 29% in the United States, and 25% in the United Kingdom), followed by topiramate, lithium, and valproate.
Nonadherence and noncompliance was common
Fewer U.K. patients (32%) reported taking their preventive therapy as advised, compared with German patients (60%) and U.S. patients (80%). Common reasons for noncompliance, regardless of location, were forgetfulness, the belief that a dose was not needed, and side effects. Most patients in the United Kingdom (60%) and the United States (54%) reported the need to take an extra dose of their acute medication to relieve pain symptoms, compared with 30% in Germany. Furthermore, 13% of U.S. patients indicated that they took extra doses all the time or nearly all the time, compared with 2% in Germany and 7% in the United Kingdom. Among patients who had discontinued a preventive treatment in the past, the most common reasons for discontinuation were lack of efficacy and problems with tolerability.
One limitation of the study was that the survey was not designed to represent the general cluster headache or treating physician populations fully. The data may reflect selection bias in favor of physicians who treat high volumes of patients and in favor of patients who frequently seek health care. In addition, the data were based on self-reports.
“Increased awareness and educational efforts that aim at promoting the need and benefit of the preventive treatment for these patients is warranted,” Dr. Andrews concluded.
Dr. Andrews is an employee of Eli Lilly, which funded the study.
SOURCE: Nichols R et al. AHS 2019. Abstract OR04.
PHILADELPHIA – , according to an analysis presented at the annual meeting of the American Headache Society.
Although consensus treatment guidelines do not exist for episodic cluster headache, treatment of this disorder did not follow many established recommendations that call for the use of preventive medications (e.g., MacGregor et al., 2010; Sarchielli et al., 2012; and May et al., 2006). Additional preventive medication options may be needed.
Patients with episodic cluster headache have several unilateral headache attacks per day. Little information is available to guide the selection of treatments for this population, and little is known about how available treatments are used in routine practice.
Analyzing cross-sectional survey data
To address this paucity of evidence, Jeffrey Scott Andrews, PharmD, a senior research scientist at Eli Lilly in Indianapolis, and colleagues examined data from the Adelphi 2017 Cluster Headache Disease Specific Programme, a large, international, cross-sectional survey. Physicians and patients in Germany, the United Kingdom, and the United States responded to the survey. Eligible physicians consulted with at least four patients with cluster headache per month, and eligible patients had a diagnosis of episodic cluster headache that was consistent with ICHD-3 beta criteria. Additional data were collected from all participants through questionnaires.
The analysis included 309 patients in Germany, 328 in the United Kingdom, and 375 in the United States. The average age of the patients was 40 years, and most of the patients were male. Less than 70% of patients reported working full time, which may indicate “the impact of this condition on work status,” said Dr. Andrews. Patients’ average number of attacks per day within an active period was 2.4. The two most commonly reported comorbidities were anxiety and depression. About 40% of cases of depression were reported to have occurred after the receipt of a diagnosis of cluster headache.
Use of inhaled oxygen was low
Most patients received acute treatments. The proportion of patients who received acute therapy only was 53% in Germany, 48% in the United Kingdom, and 43% in the United States. Approximately 34% of patients in Germany received a combination of acute and preventive therapy, compared with 37% in the United Kingdom and 42% in the United States. The proportion of patients who received preventive therapy only was 10% in Germany, 8% in the United Kingdom, and 12% in the United States.
The most commonly prescribed acute treatment, regardless of formulation, was sumatriptan. About 60% of patients received this medication. Less than one-third of patients used inhaled oxygen. Oxygen was prescribed more often in Germany (45%) and the United Kingdom (33%), compared with the United States (19%). U.S. patients face well-known obstacles in getting access to, and reimbursement for, oxygen, said Dr. Andrews. “That’s an area that deserves increased attention.” Zolmitriptan was the third most commonly prescribed acute medication.
Among prescriptions for sumatriptan, oral and injectable formulations were approximately equally common. Recommendations, however, indicate formulations with potentially fast onset of action. “The average duration of one of these attacks is between 15 and 180 minutes, so that certainly suggests that a formulation that gives you a faster onset of action might improve outcomes,” said Dr. Andrews. The use of injectable sumatriptan was lowest in the United States and highest in the United Kingdom.
“The most common decision regarding preventive treatment was [to give] no preventive treatment,” said Dr. Andrews. Verapamil was the most commonly prescribed preventive therapy (34% in Germany, 29% in the United States, and 25% in the United Kingdom), followed by topiramate, lithium, and valproate.
Nonadherence and noncompliance was common
Fewer U.K. patients (32%) reported taking their preventive therapy as advised, compared with German patients (60%) and U.S. patients (80%). Common reasons for noncompliance, regardless of location, were forgetfulness, the belief that a dose was not needed, and side effects. Most patients in the United Kingdom (60%) and the United States (54%) reported the need to take an extra dose of their acute medication to relieve pain symptoms, compared with 30% in Germany. Furthermore, 13% of U.S. patients indicated that they took extra doses all the time or nearly all the time, compared with 2% in Germany and 7% in the United Kingdom. Among patients who had discontinued a preventive treatment in the past, the most common reasons for discontinuation were lack of efficacy and problems with tolerability.
One limitation of the study was that the survey was not designed to represent the general cluster headache or treating physician populations fully. The data may reflect selection bias in favor of physicians who treat high volumes of patients and in favor of patients who frequently seek health care. In addition, the data were based on self-reports.
“Increased awareness and educational efforts that aim at promoting the need and benefit of the preventive treatment for these patients is warranted,” Dr. Andrews concluded.
Dr. Andrews is an employee of Eli Lilly, which funded the study.
SOURCE: Nichols R et al. AHS 2019. Abstract OR04.
PHILADELPHIA – , according to an analysis presented at the annual meeting of the American Headache Society.
Although consensus treatment guidelines do not exist for episodic cluster headache, treatment of this disorder did not follow many established recommendations that call for the use of preventive medications (e.g., MacGregor et al., 2010; Sarchielli et al., 2012; and May et al., 2006). Additional preventive medication options may be needed.
Patients with episodic cluster headache have several unilateral headache attacks per day. Little information is available to guide the selection of treatments for this population, and little is known about how available treatments are used in routine practice.
Analyzing cross-sectional survey data
To address this paucity of evidence, Jeffrey Scott Andrews, PharmD, a senior research scientist at Eli Lilly in Indianapolis, and colleagues examined data from the Adelphi 2017 Cluster Headache Disease Specific Programme, a large, international, cross-sectional survey. Physicians and patients in Germany, the United Kingdom, and the United States responded to the survey. Eligible physicians consulted with at least four patients with cluster headache per month, and eligible patients had a diagnosis of episodic cluster headache that was consistent with ICHD-3 beta criteria. Additional data were collected from all participants through questionnaires.
The analysis included 309 patients in Germany, 328 in the United Kingdom, and 375 in the United States. The average age of the patients was 40 years, and most of the patients were male. Less than 70% of patients reported working full time, which may indicate “the impact of this condition on work status,” said Dr. Andrews. Patients’ average number of attacks per day within an active period was 2.4. The two most commonly reported comorbidities were anxiety and depression. About 40% of cases of depression were reported to have occurred after the receipt of a diagnosis of cluster headache.
Use of inhaled oxygen was low
Most patients received acute treatments. The proportion of patients who received acute therapy only was 53% in Germany, 48% in the United Kingdom, and 43% in the United States. Approximately 34% of patients in Germany received a combination of acute and preventive therapy, compared with 37% in the United Kingdom and 42% in the United States. The proportion of patients who received preventive therapy only was 10% in Germany, 8% in the United Kingdom, and 12% in the United States.
The most commonly prescribed acute treatment, regardless of formulation, was sumatriptan. About 60% of patients received this medication. Less than one-third of patients used inhaled oxygen. Oxygen was prescribed more often in Germany (45%) and the United Kingdom (33%), compared with the United States (19%). U.S. patients face well-known obstacles in getting access to, and reimbursement for, oxygen, said Dr. Andrews. “That’s an area that deserves increased attention.” Zolmitriptan was the third most commonly prescribed acute medication.
Among prescriptions for sumatriptan, oral and injectable formulations were approximately equally common. Recommendations, however, indicate formulations with potentially fast onset of action. “The average duration of one of these attacks is between 15 and 180 minutes, so that certainly suggests that a formulation that gives you a faster onset of action might improve outcomes,” said Dr. Andrews. The use of injectable sumatriptan was lowest in the United States and highest in the United Kingdom.
“The most common decision regarding preventive treatment was [to give] no preventive treatment,” said Dr. Andrews. Verapamil was the most commonly prescribed preventive therapy (34% in Germany, 29% in the United States, and 25% in the United Kingdom), followed by topiramate, lithium, and valproate.
Nonadherence and noncompliance was common
Fewer U.K. patients (32%) reported taking their preventive therapy as advised, compared with German patients (60%) and U.S. patients (80%). Common reasons for noncompliance, regardless of location, were forgetfulness, the belief that a dose was not needed, and side effects. Most patients in the United Kingdom (60%) and the United States (54%) reported the need to take an extra dose of their acute medication to relieve pain symptoms, compared with 30% in Germany. Furthermore, 13% of U.S. patients indicated that they took extra doses all the time or nearly all the time, compared with 2% in Germany and 7% in the United Kingdom. Among patients who had discontinued a preventive treatment in the past, the most common reasons for discontinuation were lack of efficacy and problems with tolerability.
One limitation of the study was that the survey was not designed to represent the general cluster headache or treating physician populations fully. The data may reflect selection bias in favor of physicians who treat high volumes of patients and in favor of patients who frequently seek health care. In addition, the data were based on self-reports.
“Increased awareness and educational efforts that aim at promoting the need and benefit of the preventive treatment for these patients is warranted,” Dr. Andrews concluded.
Dr. Andrews is an employee of Eli Lilly, which funded the study.
SOURCE: Nichols R et al. AHS 2019. Abstract OR04.
REPORTING FROM AHS 2019
ECT breaks super-refractory status epilepticus
BANGKOK –
“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.
Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.
A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).
And realistically, these small case series are as good as the supporting evidence is likely to get.
“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.
Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.
The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm3. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.
ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.
Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.
At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.
Dr. Nguyen’s presentation met with undisguised audience skepticism.
“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.
Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.
“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.
Another audience member said the treatment strategy smacks of homeopathy.
“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.
“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.
“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.
Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.
Dr. Nguyen reported having no financial conflicts.
SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.
BANGKOK –
“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.
Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.
A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).
And realistically, these small case series are as good as the supporting evidence is likely to get.
“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.
Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.
The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm3. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.
ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.
Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.
At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.
Dr. Nguyen’s presentation met with undisguised audience skepticism.
“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.
Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.
“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.
Another audience member said the treatment strategy smacks of homeopathy.
“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.
“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.
“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.
Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.
Dr. Nguyen reported having no financial conflicts.
SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.
BANGKOK –
“These were highly refractory patients and ECT did contribute to their status termination,” she reported at the congress, sponsored by the International League Against Epilepsy.
Dr. Nguyen, a neurologist at Oregon Health and Science University, Portland, presented a single-center retrospective case series composed of four ECT-treated patients with NORSE (new onset refractory status epilepticus), three of whom experienced marked improvement in their seizure activity, including cessation of their status epilepticus, after completing a course of eight or nine ECT sessions.
A four-patient series may not seem to be compelling evidence, but it’s a significant contribution to the sparse literature regarding this off-label usage of ECT. Indeed, the biggest case series to date consists of eight patients treated at Indiana University, five of whom displayed neurotelemetry or clinical evidence of improvement within 24 hours after completing a full course of ECT (J ECT. 2018 Mar;34[1]:e5-e9. doi: 10.1097/YCT.0000000000000450).
And realistically, these small case series are as good as the supporting evidence is likely to get.
“It would be incredibly difficult to perform a randomized trial, and even a case-control study in such refractory patients would be quite difficult,” she observed.
Super-refractory status epilepticus is the term for seizures persisting despite 24 hours of adequate treatment with benzodiazepines, loading doses of antiepileptic drugs, and anesthetic agents for medically-induced coma, or for seizures that resume after withdrawal of general anesthesia. NORSE is defined as refractory status epilepticus without a history of seizures or a readily identifiable etiology. It is often associated with an autoimmune or paraneoplastic encephalitis. Outcomes are generally poor.
The four ECT-treated patients in the Oregon series were aged 27-48 years. Two had a prodromal viral illness, and a third had a vague prodrome but a negative infectious disease workup. Three patients were on four antiepileptic drugs at the time they began ECT, one was on seven. Two patients had generalized seizures, while the other two had both generalized and focal seizures. Two had normal brain MRI scans and the other two had abnormal MRIs. The patients had CSF white blood cell counts of 2, 5, 10, and 58 per mm3. All patients were on immunotherapy with intravenous corticosteroids, and three of the four were on additional immunomodulatory drugs.
ECT was started on a compassionate-use basis 16-49 days after hospital admission. These were patients who had run out of options, according to Dr. Nguyen.
Three of the four patients returned to consciousness after completing their course of ECT and withdrawal of their general anesthesia, with attenuation of their seizure activity and cessation of their super-refractory status epilepticus. Two of the three were discharged to a rehabilitation facility, including one who eventually could ambulate with slight assistance. Another patient died after discharge, while the fourth patient died during the initial hospital stay due to septic shock unrelated to the ECT.
At discharge, one patient had a modified Rankin Scale score (mRS) of 4, and two had a score of 5. At follow-up, two patients had a score of 3 and one was a 6.
Dr. Nguyen’s presentation met with undisguised audience skepticism.
“What is the theoretical basis to treat very severe epileptic seizures with another epileptic seizure? I mean, what made you do this?” one neurologist asked.
Dr. Nguyen replied that the mechanism of benefit isn’t clear. One possibility is enhanced inhibition of gamma-aminobutyric acid.
“When I describe ECT to the family, the way I think of it is as a hard reset. We tried burst suppression. This is an alternative approach,” she explained.
Another audience member said the treatment strategy smacks of homeopathy.
“These patients have a terrible disorder,” said session co-chair Gregory Krauss, MD. “Three of your four patients ultimately did not do very well.
“The question is, what are you really accomplishing in terms of the underlying encephalopathy and irritability that’s causing this? And are the seizures really a primary factor in their outcome? Is this treatment warranted to try to improve their overall outcome?” asked Dr. Krauss, professor of neurology at Johns Hopkins University, Baltimore.
Dr. Nguyen answered that she can’t say if the seizures are the cause or result of the encephalopathy.
“ECT was done well into the patients’ admission. Our difficulty is that while we were able to stop the seizures, unfortunately we weren’t able to go back in time and save the brain that was lost due to the convulsive and nonconvulsive activity,” she said. Dr. Nguyen added that she and her coinvestigators are interested in exploring the possibility that utilizing ECT earlier might abort the super-refractory status epilepticus sooner and thereby result in better outcomes.
Still, she noted, three of the four patients were able to leave the hospital, and the two survivors show improved cognitive abilities at 51 and 100 months of follow-up.
Dr. Nguyen reported having no financial conflicts.
SOURCE: Nguyen MTV et al. IEC 2019, Abstract P031.
REPORTING FROM IEC 2019
Mortality is high in pediatric superrefractory status epilepticus
BANGKOK – presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.
“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.
The study included 15 consecutive patients aged between 1 month and 17 years treated for superrefractory status epilepticus (SRSE) during 2011-2017 at the Chinese University of Hong Kong, where Dr. Yau practices. Seven children died during their index hospital admission, with a median time to death of 8 days. Two more died within several years post discharge.
Morbidity was substantial: At follow-up 1 year after the index episode of SRSE, two patients had a Glasgow Outcome Scale (GOS) score of 3, indicative of severe disability; three patients had moderate disability, with a GOS of 4; and two patients were in a vegetative state, with a GOS of 2, both of whom subsequently died of aspiration pneumonia. Only 1 of the 15 patients had a good recovery. Through 8 years of follow-up, all six survivors had epilepsy. Common nonneurologic deficits included a predisposition to a variety of infections.
By way of background, Dr. Yau noted that convulsive status epilepticus is the most common neurologic emergency in children, with an incidence of about 20 episodes per 100,000. Of affected children, 10%-40% develop refractory status, with reported mortality rates of 16%-43%. SRSE is a term reserved for persistent or recurrent seizures 24 hours or more after onset of general anesthesia for management of refractory status.
The impetus for Dr. Yau’s study was the dearth of data on SRSE in children. The literature consists of a few case series totaling well under 100 patients.
The Hong Kong case series included 15 patients with SRSE who had a median age of 7.9 years, only 1 of whom had preexisting epilepsy, a case of epileptic encephalopathy with severe developmental delay. Of the 15, 12 were boys. The patients were placed on a median of four antiepileptic drugs. Those who survived to discharge spent a median of 17.8 days under general anesthesia and 42.5 days in the pediatric ICU.
The SRSE etiologies included febrile infection–related epilepsy syndrome in two cases, four serious infections, four cases of autoimmune etiology, two cases of epileptic encephalopathy, one patient with hypoxia caused by severe croup, and two of unknown origin despite intensive work-up.
The four in-hospital deaths caused by acute cerebral edema occurred a median 6.5 days after admission. There were also two deaths because of uncontrolled sepsis and one because of intraventricular bleeding secondary to thrombotic thrombocytopenic purpura thought to have occurred as a complication of interactions between the numerous prescribed medications. All six children with an infectious or unknown etiology died in hospital, whereas none of those with an autoimmune etiology, epileptic encephalopathy, or hypoxia did. Duration of anesthesia did not predict mortality.
Other investigators have reported that younger age is associated with higher mortality, but that was not true in the Hong Kong experience. Neither of the two children aged less than 3 years died during their index hospitalization. All 7 deaths occurred in the 13 children age 3 years or older.
When asked whether she thought SRSE or the underlying disorder was the bigger contributor to mortality, Dr. Yau replied that she believes the prolonged refractory seizures may have worsened cerebral edema in some patients and thereby have been the cause of death.
She reported having no financial conflicts regarding her study.
BANGKOK – presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.
“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.
The study included 15 consecutive patients aged between 1 month and 17 years treated for superrefractory status epilepticus (SRSE) during 2011-2017 at the Chinese University of Hong Kong, where Dr. Yau practices. Seven children died during their index hospital admission, with a median time to death of 8 days. Two more died within several years post discharge.
Morbidity was substantial: At follow-up 1 year after the index episode of SRSE, two patients had a Glasgow Outcome Scale (GOS) score of 3, indicative of severe disability; three patients had moderate disability, with a GOS of 4; and two patients were in a vegetative state, with a GOS of 2, both of whom subsequently died of aspiration pneumonia. Only 1 of the 15 patients had a good recovery. Through 8 years of follow-up, all six survivors had epilepsy. Common nonneurologic deficits included a predisposition to a variety of infections.
By way of background, Dr. Yau noted that convulsive status epilepticus is the most common neurologic emergency in children, with an incidence of about 20 episodes per 100,000. Of affected children, 10%-40% develop refractory status, with reported mortality rates of 16%-43%. SRSE is a term reserved for persistent or recurrent seizures 24 hours or more after onset of general anesthesia for management of refractory status.
The impetus for Dr. Yau’s study was the dearth of data on SRSE in children. The literature consists of a few case series totaling well under 100 patients.
The Hong Kong case series included 15 patients with SRSE who had a median age of 7.9 years, only 1 of whom had preexisting epilepsy, a case of epileptic encephalopathy with severe developmental delay. Of the 15, 12 were boys. The patients were placed on a median of four antiepileptic drugs. Those who survived to discharge spent a median of 17.8 days under general anesthesia and 42.5 days in the pediatric ICU.
The SRSE etiologies included febrile infection–related epilepsy syndrome in two cases, four serious infections, four cases of autoimmune etiology, two cases of epileptic encephalopathy, one patient with hypoxia caused by severe croup, and two of unknown origin despite intensive work-up.
The four in-hospital deaths caused by acute cerebral edema occurred a median 6.5 days after admission. There were also two deaths because of uncontrolled sepsis and one because of intraventricular bleeding secondary to thrombotic thrombocytopenic purpura thought to have occurred as a complication of interactions between the numerous prescribed medications. All six children with an infectious or unknown etiology died in hospital, whereas none of those with an autoimmune etiology, epileptic encephalopathy, or hypoxia did. Duration of anesthesia did not predict mortality.
Other investigators have reported that younger age is associated with higher mortality, but that was not true in the Hong Kong experience. Neither of the two children aged less than 3 years died during their index hospitalization. All 7 deaths occurred in the 13 children age 3 years or older.
When asked whether she thought SRSE or the underlying disorder was the bigger contributor to mortality, Dr. Yau replied that she believes the prolonged refractory seizures may have worsened cerebral edema in some patients and thereby have been the cause of death.
She reported having no financial conflicts regarding her study.
BANGKOK – presented by Maggie Lo Yee Yau, MD, at the International Epilepsy Congress.
“Death in these children usually occurred within the first few days after admission to the pediatric ICU,” she said at the congress sponsored by the International League Against Epilepsy.
The study included 15 consecutive patients aged between 1 month and 17 years treated for superrefractory status epilepticus (SRSE) during 2011-2017 at the Chinese University of Hong Kong, where Dr. Yau practices. Seven children died during their index hospital admission, with a median time to death of 8 days. Two more died within several years post discharge.
Morbidity was substantial: At follow-up 1 year after the index episode of SRSE, two patients had a Glasgow Outcome Scale (GOS) score of 3, indicative of severe disability; three patients had moderate disability, with a GOS of 4; and two patients were in a vegetative state, with a GOS of 2, both of whom subsequently died of aspiration pneumonia. Only 1 of the 15 patients had a good recovery. Through 8 years of follow-up, all six survivors had epilepsy. Common nonneurologic deficits included a predisposition to a variety of infections.
By way of background, Dr. Yau noted that convulsive status epilepticus is the most common neurologic emergency in children, with an incidence of about 20 episodes per 100,000. Of affected children, 10%-40% develop refractory status, with reported mortality rates of 16%-43%. SRSE is a term reserved for persistent or recurrent seizures 24 hours or more after onset of general anesthesia for management of refractory status.
The impetus for Dr. Yau’s study was the dearth of data on SRSE in children. The literature consists of a few case series totaling well under 100 patients.
The Hong Kong case series included 15 patients with SRSE who had a median age of 7.9 years, only 1 of whom had preexisting epilepsy, a case of epileptic encephalopathy with severe developmental delay. Of the 15, 12 were boys. The patients were placed on a median of four antiepileptic drugs. Those who survived to discharge spent a median of 17.8 days under general anesthesia and 42.5 days in the pediatric ICU.
The SRSE etiologies included febrile infection–related epilepsy syndrome in two cases, four serious infections, four cases of autoimmune etiology, two cases of epileptic encephalopathy, one patient with hypoxia caused by severe croup, and two of unknown origin despite intensive work-up.
The four in-hospital deaths caused by acute cerebral edema occurred a median 6.5 days after admission. There were also two deaths because of uncontrolled sepsis and one because of intraventricular bleeding secondary to thrombotic thrombocytopenic purpura thought to have occurred as a complication of interactions between the numerous prescribed medications. All six children with an infectious or unknown etiology died in hospital, whereas none of those with an autoimmune etiology, epileptic encephalopathy, or hypoxia did. Duration of anesthesia did not predict mortality.
Other investigators have reported that younger age is associated with higher mortality, but that was not true in the Hong Kong experience. Neither of the two children aged less than 3 years died during their index hospitalization. All 7 deaths occurred in the 13 children age 3 years or older.
When asked whether she thought SRSE or the underlying disorder was the bigger contributor to mortality, Dr. Yau replied that she believes the prolonged refractory seizures may have worsened cerebral edema in some patients and thereby have been the cause of death.
She reported having no financial conflicts regarding her study.
REPORTING FROM IEC 2019
Neonatal epileptic syndromes are surprisingly common
BANGKOK – Katherine B. Howell, MD, reported at the International Epilepsy Congress.
“This is an important finding. It’s a considerably larger number than might have been expected and likely has two contributing factors. Neonatal seizures were previously not considered epilepsy, so many previous studies excluded neonates and the conditions were underrecognized. And our large number of ictal EEGs allowed identification of ictal activation, which is a feature of EIMFS [epilepsy of infancy with migrating focal seizures]. Without those ictal recordings, the diagnosis of EIMFS may not have been made,” according to Dr. Howell, a neurologist at the Royal Children’s Hospital and University of Melbourne.
She presented a population-based study of all infants born with severe epilepsies of infancy (SEI) during a 2-year period in the Australian state of Victoria, which is considered an ideal environment for epidemiologic studies because government-funded health care is available to all. SEI was defined as seizures beginning before age 18 months, occurring at a rate of at least one per day for 1 week or weekly for 1 month, refractory to adequate trials of at least two antiepileptic drugs, and accompanied by an epileptiform EEG abnormality. Her focus was on the electroclinical phenotypes of the affected children because of the high clinical utility of this information.
“Assigning an epileptic syndrome is highly useful for clinician-to-clinician communication of an infant’s phenotype. It guides investigation of etiology and possibly selection of optimal therapy, such as steroids in West syndrome. And it can inform prognosis,” Dr. Howell said at the congress sponsored by the International League Against Epilepsy.
She and her coinvestigators analyzed the detailed records of all 114 infants with SEI born during the study period. The incidence was 1 in 2,000 live births.
“Among infants with epilepsy, this patient group with SEI is most critical to better understand. Effective treatment is often not available, the seizure and developmental outcomes are frequently devastating, and the health burden massive,” the neurologist observed.
The full spectrum of SEI
With the help of ictal EEGs, home seizure recordings, MRI scans, and genomic testing, the investigators were able to classify more than 85% of the infants. About 64% had a prototypic syndrome at onset, such as West syndrome, which accounted for 33% of all SEI, or Dravet syndrome, which was diagnosed in 3%.
The prevalence of the prototypic neonatal and early infantile epileptic syndromes was notably higher than previously reported by others: EIMFS accounted for 9% of total SEI, early infantile epileptic encephalopathy (EIEE) for 7%, and early myoclonic encephalopathy (EME) for 2%. This translated to an incidence of 1 in 28,000 live births for EIEE, 1 in 111,000 for EME, and 1 in 22,500 for EIMFS.
“While neither EIEE nor EIMFS are common, these incidences are actually not that much lower than the reported incidence of Dravet syndrome,” the neurologist pointed out.
About 36% of SEI didn’t fit into any of the prototypic syndromes. However, more than half of this subgroup, or 19% of total SEI, were prototypic syndrome like, a designation Dr. Howell and her coworkers used for cases that possessed most but not all of the well-recognized features of a particular prototypic syndrome; for example, West syndrome–like seizures but without hypsarrhythmia. Whether these prototypic syndrome-like SEI have etiologies and outcomes similar to or distinct from the prototypic syndromes remains a topic for further study.
SEI etiologies
A total of 14 patients had SEI because of an acquired syndrome attributed to brain injury, 31 were because of brain malformation, 21 involved single gene disorders, 9 were of chromosomal etiology, and 7 had a metabolic cause.
The key finding with regard to etiology was the glaring difference between children with West syndrome, its variants, or unifocal epilepsies as compared with the rest of the SEI patients. Those with West syndrome, a West syndrome–like designation, or unifocal epilepsies most commonly had a structural etiology for their SEI. Indeed, of the 52 children with West syndrome or a variant, 10 had an acquired brain injury as their etiology and 17 had a brain malformation. And of the 12 patients with unifocal SEI, 1 had a brain injury and 9 had brain malformations.
In contrast, children with neonatal or early infantile epileptic syndromes had predominantly genetic rather than structural etiologies. Of the 20 children with EIEE, EIMFS, or EME, none had brain injury as the etiology, only 1 had a brain malformation, but 9 had a single gene or chromosomal etiology.
Outcomes
“The outcome data highlight the extreme severity of SEI and the imperative for novel treatments: 16% mortality overall, so one in six was deceased by age 2 years. The infants who died after the neonatal period all had profound delays, and almost all had ongoing seizures until their death. Most survivors also had developmental delay, with severity ranging from mild to moderate in 49% to severe/profound in 41%. Just 10 of 114 children had normal development,” Dr. Howell reported.
However, there was a notable difference in outcomes between the various syndromes, and this information is highly relevant prognostically. Of the 20 children with neonatal and early infantile epileptic syndromes, 11 died and the other 9 had profound developmental delay. In contrast, the outlook was far better for children with West syndrome, West syndrome–like variants, or focal epilepsies: Among 64 affected patients, there were just 2 deaths, normal development in 9 patients, mild to moderate developmental delay in 34, and severe/profound delay in 19.
Dr. Howell reported having no financial conflicts regarding this study, which was supported by governmental research grants.
bjancin@mdedge.com
SOURCE: Howell KB et al. IEC 2019, Abstract P053.
BANGKOK – Katherine B. Howell, MD, reported at the International Epilepsy Congress.
“This is an important finding. It’s a considerably larger number than might have been expected and likely has two contributing factors. Neonatal seizures were previously not considered epilepsy, so many previous studies excluded neonates and the conditions were underrecognized. And our large number of ictal EEGs allowed identification of ictal activation, which is a feature of EIMFS [epilepsy of infancy with migrating focal seizures]. Without those ictal recordings, the diagnosis of EIMFS may not have been made,” according to Dr. Howell, a neurologist at the Royal Children’s Hospital and University of Melbourne.
She presented a population-based study of all infants born with severe epilepsies of infancy (SEI) during a 2-year period in the Australian state of Victoria, which is considered an ideal environment for epidemiologic studies because government-funded health care is available to all. SEI was defined as seizures beginning before age 18 months, occurring at a rate of at least one per day for 1 week or weekly for 1 month, refractory to adequate trials of at least two antiepileptic drugs, and accompanied by an epileptiform EEG abnormality. Her focus was on the electroclinical phenotypes of the affected children because of the high clinical utility of this information.
“Assigning an epileptic syndrome is highly useful for clinician-to-clinician communication of an infant’s phenotype. It guides investigation of etiology and possibly selection of optimal therapy, such as steroids in West syndrome. And it can inform prognosis,” Dr. Howell said at the congress sponsored by the International League Against Epilepsy.
She and her coinvestigators analyzed the detailed records of all 114 infants with SEI born during the study period. The incidence was 1 in 2,000 live births.
“Among infants with epilepsy, this patient group with SEI is most critical to better understand. Effective treatment is often not available, the seizure and developmental outcomes are frequently devastating, and the health burden massive,” the neurologist observed.
The full spectrum of SEI
With the help of ictal EEGs, home seizure recordings, MRI scans, and genomic testing, the investigators were able to classify more than 85% of the infants. About 64% had a prototypic syndrome at onset, such as West syndrome, which accounted for 33% of all SEI, or Dravet syndrome, which was diagnosed in 3%.
The prevalence of the prototypic neonatal and early infantile epileptic syndromes was notably higher than previously reported by others: EIMFS accounted for 9% of total SEI, early infantile epileptic encephalopathy (EIEE) for 7%, and early myoclonic encephalopathy (EME) for 2%. This translated to an incidence of 1 in 28,000 live births for EIEE, 1 in 111,000 for EME, and 1 in 22,500 for EIMFS.
“While neither EIEE nor EIMFS are common, these incidences are actually not that much lower than the reported incidence of Dravet syndrome,” the neurologist pointed out.
About 36% of SEI didn’t fit into any of the prototypic syndromes. However, more than half of this subgroup, or 19% of total SEI, were prototypic syndrome like, a designation Dr. Howell and her coworkers used for cases that possessed most but not all of the well-recognized features of a particular prototypic syndrome; for example, West syndrome–like seizures but without hypsarrhythmia. Whether these prototypic syndrome-like SEI have etiologies and outcomes similar to or distinct from the prototypic syndromes remains a topic for further study.
SEI etiologies
A total of 14 patients had SEI because of an acquired syndrome attributed to brain injury, 31 were because of brain malformation, 21 involved single gene disorders, 9 were of chromosomal etiology, and 7 had a metabolic cause.
The key finding with regard to etiology was the glaring difference between children with West syndrome, its variants, or unifocal epilepsies as compared with the rest of the SEI patients. Those with West syndrome, a West syndrome–like designation, or unifocal epilepsies most commonly had a structural etiology for their SEI. Indeed, of the 52 children with West syndrome or a variant, 10 had an acquired brain injury as their etiology and 17 had a brain malformation. And of the 12 patients with unifocal SEI, 1 had a brain injury and 9 had brain malformations.
In contrast, children with neonatal or early infantile epileptic syndromes had predominantly genetic rather than structural etiologies. Of the 20 children with EIEE, EIMFS, or EME, none had brain injury as the etiology, only 1 had a brain malformation, but 9 had a single gene or chromosomal etiology.
Outcomes
“The outcome data highlight the extreme severity of SEI and the imperative for novel treatments: 16% mortality overall, so one in six was deceased by age 2 years. The infants who died after the neonatal period all had profound delays, and almost all had ongoing seizures until their death. Most survivors also had developmental delay, with severity ranging from mild to moderate in 49% to severe/profound in 41%. Just 10 of 114 children had normal development,” Dr. Howell reported.
However, there was a notable difference in outcomes between the various syndromes, and this information is highly relevant prognostically. Of the 20 children with neonatal and early infantile epileptic syndromes, 11 died and the other 9 had profound developmental delay. In contrast, the outlook was far better for children with West syndrome, West syndrome–like variants, or focal epilepsies: Among 64 affected patients, there were just 2 deaths, normal development in 9 patients, mild to moderate developmental delay in 34, and severe/profound delay in 19.
Dr. Howell reported having no financial conflicts regarding this study, which was supported by governmental research grants.
bjancin@mdedge.com
SOURCE: Howell KB et al. IEC 2019, Abstract P053.
BANGKOK – Katherine B. Howell, MD, reported at the International Epilepsy Congress.
“This is an important finding. It’s a considerably larger number than might have been expected and likely has two contributing factors. Neonatal seizures were previously not considered epilepsy, so many previous studies excluded neonates and the conditions were underrecognized. And our large number of ictal EEGs allowed identification of ictal activation, which is a feature of EIMFS [epilepsy of infancy with migrating focal seizures]. Without those ictal recordings, the diagnosis of EIMFS may not have been made,” according to Dr. Howell, a neurologist at the Royal Children’s Hospital and University of Melbourne.
She presented a population-based study of all infants born with severe epilepsies of infancy (SEI) during a 2-year period in the Australian state of Victoria, which is considered an ideal environment for epidemiologic studies because government-funded health care is available to all. SEI was defined as seizures beginning before age 18 months, occurring at a rate of at least one per day for 1 week or weekly for 1 month, refractory to adequate trials of at least two antiepileptic drugs, and accompanied by an epileptiform EEG abnormality. Her focus was on the electroclinical phenotypes of the affected children because of the high clinical utility of this information.
“Assigning an epileptic syndrome is highly useful for clinician-to-clinician communication of an infant’s phenotype. It guides investigation of etiology and possibly selection of optimal therapy, such as steroids in West syndrome. And it can inform prognosis,” Dr. Howell said at the congress sponsored by the International League Against Epilepsy.
She and her coinvestigators analyzed the detailed records of all 114 infants with SEI born during the study period. The incidence was 1 in 2,000 live births.
“Among infants with epilepsy, this patient group with SEI is most critical to better understand. Effective treatment is often not available, the seizure and developmental outcomes are frequently devastating, and the health burden massive,” the neurologist observed.
The full spectrum of SEI
With the help of ictal EEGs, home seizure recordings, MRI scans, and genomic testing, the investigators were able to classify more than 85% of the infants. About 64% had a prototypic syndrome at onset, such as West syndrome, which accounted for 33% of all SEI, or Dravet syndrome, which was diagnosed in 3%.
The prevalence of the prototypic neonatal and early infantile epileptic syndromes was notably higher than previously reported by others: EIMFS accounted for 9% of total SEI, early infantile epileptic encephalopathy (EIEE) for 7%, and early myoclonic encephalopathy (EME) for 2%. This translated to an incidence of 1 in 28,000 live births for EIEE, 1 in 111,000 for EME, and 1 in 22,500 for EIMFS.
“While neither EIEE nor EIMFS are common, these incidences are actually not that much lower than the reported incidence of Dravet syndrome,” the neurologist pointed out.
About 36% of SEI didn’t fit into any of the prototypic syndromes. However, more than half of this subgroup, or 19% of total SEI, were prototypic syndrome like, a designation Dr. Howell and her coworkers used for cases that possessed most but not all of the well-recognized features of a particular prototypic syndrome; for example, West syndrome–like seizures but without hypsarrhythmia. Whether these prototypic syndrome-like SEI have etiologies and outcomes similar to or distinct from the prototypic syndromes remains a topic for further study.
SEI etiologies
A total of 14 patients had SEI because of an acquired syndrome attributed to brain injury, 31 were because of brain malformation, 21 involved single gene disorders, 9 were of chromosomal etiology, and 7 had a metabolic cause.
The key finding with regard to etiology was the glaring difference between children with West syndrome, its variants, or unifocal epilepsies as compared with the rest of the SEI patients. Those with West syndrome, a West syndrome–like designation, or unifocal epilepsies most commonly had a structural etiology for their SEI. Indeed, of the 52 children with West syndrome or a variant, 10 had an acquired brain injury as their etiology and 17 had a brain malformation. And of the 12 patients with unifocal SEI, 1 had a brain injury and 9 had brain malformations.
In contrast, children with neonatal or early infantile epileptic syndromes had predominantly genetic rather than structural etiologies. Of the 20 children with EIEE, EIMFS, or EME, none had brain injury as the etiology, only 1 had a brain malformation, but 9 had a single gene or chromosomal etiology.
Outcomes
“The outcome data highlight the extreme severity of SEI and the imperative for novel treatments: 16% mortality overall, so one in six was deceased by age 2 years. The infants who died after the neonatal period all had profound delays, and almost all had ongoing seizures until their death. Most survivors also had developmental delay, with severity ranging from mild to moderate in 49% to severe/profound in 41%. Just 10 of 114 children had normal development,” Dr. Howell reported.
However, there was a notable difference in outcomes between the various syndromes, and this information is highly relevant prognostically. Of the 20 children with neonatal and early infantile epileptic syndromes, 11 died and the other 9 had profound developmental delay. In contrast, the outlook was far better for children with West syndrome, West syndrome–like variants, or focal epilepsies: Among 64 affected patients, there were just 2 deaths, normal development in 9 patients, mild to moderate developmental delay in 34, and severe/profound delay in 19.
Dr. Howell reported having no financial conflicts regarding this study, which was supported by governmental research grants.
bjancin@mdedge.com
SOURCE: Howell KB et al. IEC 2019, Abstract P053.
REPORTING FROM IEC 2019
Quarterly intravenous eptinezumab prevents migraine
PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.
In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.
Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.
The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.
In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.
Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.
Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.
The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.
PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.
SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12
PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.
In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.
Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.
The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.
In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.
Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.
Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.
The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.
PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.
SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12
PHILADELPHIA – An intravenous formulation of a calcitonin gene–related peptide inhibitor monoclonal antibody showed efficacy for preventing chronic migraine headaches for 3 months in a dose-ranging, phase 3 trial with 1,072 patients.
In a separate study with 669 patients, a single IV dose of the antibody, eptinezumab, also significantly reduced the incidence of episodic migraine headaches during 3 months of follow-up, compared with placebo. And in both the chronic and episodic migraine studies a similar 3-month effect resulted from a second IV dose of the humanized antibody that binds the calcitonin gene–related peptide (CGRP) ligand, thereby blocking the pathway, Laszlo L. Mechtler, MD, and his associates reported in a poster at the annual meeting of the American Headache Society.
Eptinezumab follows the therapeutic approach already used by three Food and Drug Administration–approved monoclonal antibody drugs that cut migraine headache recurrences by blocking the CGRP pathway by binding either the peptide ligand or its receptor: erenumab-aooe (Aimovig), fremanezumab-vfrm (Ajovy), and galcanezumab-gnlm (Emgality). Eptinezumab differs from the three approved CGRP antibodies by using an IV route of administration – the other three are delivered by subcutaneous injection – and by a 3-month dosing interval. Both erenumab-aooe and galcanezumab-gnlm are labeled for monthly administration only, while fremanezumab-vfrm is labeled for both monthly and once every 3 months dosing schedules.
The PROMISE-1 (A Multicenter Assessment of ALD403 in Frequent Episodic Migraine) trial randomized 669 patients with episodic migraine (defined as 4-14 headache days/month with at least 4 classifiable as migraine headache days) at 87 centers mostly in the United States and with some in Georgia. The PROMISE-2 (Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine) trial randomized 1,072 patients with chronic migraine (defined as a history of 15-26 headache days/month and with at least 8 of the days involving a migraine headache) at any of 145 study sites, many in the United States, in several countries.
In PROMISE-1, patients could receive as many as four serial infusions every 3 months, and up to two serial infusions in PROMISE-2, but the primary endpoint in both studies was the change in monthly migraine count from baseline during the 3 months following the first dosage.
Among patients with chronic migraine in PROMISE-2, the average monthly migraine number fell by 8.2 migraine days/month, compared with an average 5.6 monthly migraine days drop from baseline among placebo patients, which was a statistically significant difference for the higher dosage of eptinezumab tested, 300 mg. A 100-mg dose linked with an average 7.7 migraine days/month reduction, also a statistically significant difference from the placebo patients, reported Dr. Mechtler, professor of neurology at the State University of New York at Buffalo and medical director of the Dent Neurologic Institute in Buffalo, and his associates.
Among patients with episodic migraine in PROMISE-1, the 300-mg dosage cut monthly migraines by an average 4.3 migraine headache days/month, compared with 3.2 in the placebo group, a statistically significant difference. Among patients who received the 100-mg dosage, the average cut was 3.9 migraine headache days/month, also a statistically significant difference from the placebo controls.
The researchers included no safety findings in their report, but in an interview Dr. Mechtler said that eptinezumab showed an excellent safety profile that was consistent with what’s been previously reported for the approved agents from this class. He cited the safety of the drugs in the class as a major feature of their clinical utility.
PROMISE-1 and PROMISE-2 were sponsored by Alder BioPharmaceuticals, the company developing eptinezumab. Dr. Mechtler has been a speaker on behalf of Allergan, Amgen/Novartis, Boston Biomedical, Promius, Avanir, and Teva, and he has received research funding from Allergan, Autonomic Technologies, Boston Biomedical, and Teva.
SOURCE: Mechtler LL et al. Headache. 2019 June;59[S1]:34, Abstract P12
REPORTING FROM AHS 2019
Mediterranean diet tied to improved cognition in type 2 diabetes
People with type 2 diabetes whose diet followed a “Mediterranean” pattern – high in vegetables, legumes, fish, and unsaturated fats – saw global cognitive improvements over a 2-year period, compared with individuals with different eating patterns, even if the latter incorporated healthy dietary features. In addition, effective glycemic control seemed to have a role in sustaining the benefits associated with the Mediterranean-type diet.
Adults without type 2 diabetes, meanwhile, did not see the cognitive improvements associated with a Mediterranean diet, suggesting that the pathways linking diet to cognition may be different for individuals with and without diabetes, according to Josiemer Mattei, PhD, of the Harvard T.H. Chan School of Public Health in Boston and colleagues.
The investigators used data from the Boston Puerto Rican Health Study, a longitudinal cohort of about 1,499 adults aged 45-75 years who lived in Boston and identified as Puerto Rican, for their research, which was published in Diabetes Care.
At baseline, participants were administered a questionnaire to capture their eating patterns. Four diet-quality scores – Mediterranean Diet Score, Healthy Eating Index, Alternate Healthy Eating Index, and DASH (Dietary Approaches to Stop Hypertension) were analyzed. The participants were also screened for diabetes, and nearly 40% of them were found to have type 2 diabetes at baseline (74% uncontrolled). They underwent a battery of cognitive tests, including the Mini-Mental State Exam and tests for verbal fluency, executive function, word recognition, and figure copying. The study endpoints included 2-year change in global cognitive function as well as executive and memory function. At 2 years, data was available for 913 participants.
Among participants with type 2 diabetes, greater adherence to a Mediterranean-style diet was significantly associated with a higher positive change at the 2-year follow-up in global cognitive function score (0.027 [SD, 0.011]; P = .016), the Mini-Mental State Exam, and other individual tests. The association was significant for those who were under glycemic control at baseline and who remained stable or improved over 2 years, but not for those with poor or worsening glycemic control.
“The Mediterranean diet explained as much or more of the variability in predicting changes in cognitive function in our study as did age, especially for participants with type 2 diabetes under glycemic control. ... This dietary pattern may provide more cognitive benefits [in this patient group] than other modifiable and nonmodifiable factors,” the authors wrote in their analysis. They stressed that a Mediterranean dietary pattern can be realized through foods and dishes that are already standard in many Puerto Rican households.
In participants who did not have diabetes, improvement in memory function measures was seen in association with a Mediterranean diet, but also with adherence to other eating patterns that are deemed healthy. That suggests that for this subgroup, any evidence-based healthy diet – not just the Mediterranean diet – may have some benefits for memory function.
“Dietary recommendations for cognitive health may need to be tailored for individuals with versus without type 2 diabetes,” the authors concluded.
Dr. Mattei and colleagues acknowledged as a limitation of their study its observational design.
The study received funding from the National Heart, Lung, and Blood Institute; the National Institute on Aging; and Harvard University. The authors reported no financial conflicts of interest.
SOURCE: Mattei et al. Diabetes Care. 2019;42(8):1372-9.
People with type 2 diabetes whose diet followed a “Mediterranean” pattern – high in vegetables, legumes, fish, and unsaturated fats – saw global cognitive improvements over a 2-year period, compared with individuals with different eating patterns, even if the latter incorporated healthy dietary features. In addition, effective glycemic control seemed to have a role in sustaining the benefits associated with the Mediterranean-type diet.
Adults without type 2 diabetes, meanwhile, did not see the cognitive improvements associated with a Mediterranean diet, suggesting that the pathways linking diet to cognition may be different for individuals with and without diabetes, according to Josiemer Mattei, PhD, of the Harvard T.H. Chan School of Public Health in Boston and colleagues.
The investigators used data from the Boston Puerto Rican Health Study, a longitudinal cohort of about 1,499 adults aged 45-75 years who lived in Boston and identified as Puerto Rican, for their research, which was published in Diabetes Care.
At baseline, participants were administered a questionnaire to capture their eating patterns. Four diet-quality scores – Mediterranean Diet Score, Healthy Eating Index, Alternate Healthy Eating Index, and DASH (Dietary Approaches to Stop Hypertension) were analyzed. The participants were also screened for diabetes, and nearly 40% of them were found to have type 2 diabetes at baseline (74% uncontrolled). They underwent a battery of cognitive tests, including the Mini-Mental State Exam and tests for verbal fluency, executive function, word recognition, and figure copying. The study endpoints included 2-year change in global cognitive function as well as executive and memory function. At 2 years, data was available for 913 participants.
Among participants with type 2 diabetes, greater adherence to a Mediterranean-style diet was significantly associated with a higher positive change at the 2-year follow-up in global cognitive function score (0.027 [SD, 0.011]; P = .016), the Mini-Mental State Exam, and other individual tests. The association was significant for those who were under glycemic control at baseline and who remained stable or improved over 2 years, but not for those with poor or worsening glycemic control.
“The Mediterranean diet explained as much or more of the variability in predicting changes in cognitive function in our study as did age, especially for participants with type 2 diabetes under glycemic control. ... This dietary pattern may provide more cognitive benefits [in this patient group] than other modifiable and nonmodifiable factors,” the authors wrote in their analysis. They stressed that a Mediterranean dietary pattern can be realized through foods and dishes that are already standard in many Puerto Rican households.
In participants who did not have diabetes, improvement in memory function measures was seen in association with a Mediterranean diet, but also with adherence to other eating patterns that are deemed healthy. That suggests that for this subgroup, any evidence-based healthy diet – not just the Mediterranean diet – may have some benefits for memory function.
“Dietary recommendations for cognitive health may need to be tailored for individuals with versus without type 2 diabetes,” the authors concluded.
Dr. Mattei and colleagues acknowledged as a limitation of their study its observational design.
The study received funding from the National Heart, Lung, and Blood Institute; the National Institute on Aging; and Harvard University. The authors reported no financial conflicts of interest.
SOURCE: Mattei et al. Diabetes Care. 2019;42(8):1372-9.
People with type 2 diabetes whose diet followed a “Mediterranean” pattern – high in vegetables, legumes, fish, and unsaturated fats – saw global cognitive improvements over a 2-year period, compared with individuals with different eating patterns, even if the latter incorporated healthy dietary features. In addition, effective glycemic control seemed to have a role in sustaining the benefits associated with the Mediterranean-type diet.
Adults without type 2 diabetes, meanwhile, did not see the cognitive improvements associated with a Mediterranean diet, suggesting that the pathways linking diet to cognition may be different for individuals with and without diabetes, according to Josiemer Mattei, PhD, of the Harvard T.H. Chan School of Public Health in Boston and colleagues.
The investigators used data from the Boston Puerto Rican Health Study, a longitudinal cohort of about 1,499 adults aged 45-75 years who lived in Boston and identified as Puerto Rican, for their research, which was published in Diabetes Care.
At baseline, participants were administered a questionnaire to capture their eating patterns. Four diet-quality scores – Mediterranean Diet Score, Healthy Eating Index, Alternate Healthy Eating Index, and DASH (Dietary Approaches to Stop Hypertension) were analyzed. The participants were also screened for diabetes, and nearly 40% of them were found to have type 2 diabetes at baseline (74% uncontrolled). They underwent a battery of cognitive tests, including the Mini-Mental State Exam and tests for verbal fluency, executive function, word recognition, and figure copying. The study endpoints included 2-year change in global cognitive function as well as executive and memory function. At 2 years, data was available for 913 participants.
Among participants with type 2 diabetes, greater adherence to a Mediterranean-style diet was significantly associated with a higher positive change at the 2-year follow-up in global cognitive function score (0.027 [SD, 0.011]; P = .016), the Mini-Mental State Exam, and other individual tests. The association was significant for those who were under glycemic control at baseline and who remained stable or improved over 2 years, but not for those with poor or worsening glycemic control.
“The Mediterranean diet explained as much or more of the variability in predicting changes in cognitive function in our study as did age, especially for participants with type 2 diabetes under glycemic control. ... This dietary pattern may provide more cognitive benefits [in this patient group] than other modifiable and nonmodifiable factors,” the authors wrote in their analysis. They stressed that a Mediterranean dietary pattern can be realized through foods and dishes that are already standard in many Puerto Rican households.
In participants who did not have diabetes, improvement in memory function measures was seen in association with a Mediterranean diet, but also with adherence to other eating patterns that are deemed healthy. That suggests that for this subgroup, any evidence-based healthy diet – not just the Mediterranean diet – may have some benefits for memory function.
“Dietary recommendations for cognitive health may need to be tailored for individuals with versus without type 2 diabetes,” the authors concluded.
Dr. Mattei and colleagues acknowledged as a limitation of their study its observational design.
The study received funding from the National Heart, Lung, and Blood Institute; the National Institute on Aging; and Harvard University. The authors reported no financial conflicts of interest.
SOURCE: Mattei et al. Diabetes Care. 2019;42(8):1372-9.
FROM DIABETES CARE
Epilepsy surgery outcome prediction seeks to gain ground
BANGKOK –
She and her colleagues have created and validated an online risk prediction tool that clinicians can use to predict a patient’s individualized likelihood of complete freedom from seizures 2 and 5 years after undergoing resective brain surgery for drug-resistant epilepsy. The risk predictor, known as the Epilepsy Surgery Nomogram, uses a handful of simple clinical characteristics – patient gender, pathologic cause of the seizures, the proposed type of epilepsy surgery, the presence or absence of generalized tonic-clonic seizures, epilepsy duration, and preoperative seizure frequency – and spits out the patient’s predicted seizure outcome, she explained at the congress, sponsored by the International League Against Epilepsy.
“The point here is that every patient is an individual. And to give people predictions based on 500- or 600-patient Kaplan-Meier-derived curves that just provide the average outcome for the whole cohort isn’t really going to give them what they need as far as their individualized chance of becoming seizure free,” said Dr. Jehi, a neurologist at the Cleveland Clinic.
Similarly, reliance solely upon clinical judgment is a minefield. Multiple biases prevent physicians from making objective medical predictions, she continued.
“We think of the process of medical decision-making and outcome prediction as being a process that is logical and rational, where the accumulation of knowledge improves the decisions that we make, and where past experience improves judgment, and where collective decisions are more reliable. This is what intuitively we all think. That’s why we think we are invincible as physicians. And to that I say, really? There is a wealth of literature that actually disproves each one of these points,” Dr. Jehi declared.
Outcomes of brain surgery for drug-resistant epilepsy have remained static for more than half a century: Ten years after surgery, roughly half of treated patients remain completely seizure free. The inability of clinicians to use advanced statistics to inform potential surgical candidates about their individualized chance of becoming seizure free has probably contributed to underutilization of epilepsy surgery, she added.
The Epilepsy Surgery Nomogram was developed through detailed analysis of the records of 846 patients who underwent epilepsy surgery at the Cleveland Clinic. The resultant nomogram was then validated in a cohort of 604 patients who had resective surgery at the Mayo Clinic and epilepsy surgery centers in Brazil, Italy, and France. In the development cohort, the rate of complete freedom from seizures was 57% at 2 years and 40% at 5 years. In the validation study, the nomogram had a concordance statistic of 0.60 for complete freedom from seizures, which is considered better than chance, but well below the 0.80 threshold defined as strong concordance (Lancet Neurol. 2015 Mar;14[3]:283-90).
However, in an era when personalized medicine has become a catch phrase, the Epilepsy Surgery Nomogram has captured the attention of officials at the National Institutes of Health. Indeed, Dr. Jehi and her coworkers have received a $3.4 million, 5-year grant from the NIH to improve their risk prediction model by incorporating additional variables, including EEG data, MRI findings, family history, and genetic information. The enhanced risk calculator also will include a predictor of the likelihood that an individual will experience clinically meaningful improvement in quality of life in response to epilepsy surgery, since that’s an important outcome even in the absence of 100% freedom from seizures.
Recently, Dr. Jehi and coworkers have developed and then externally validated nomograms to predict the individualized risk of clinically relevant postoperative naming decline after temporal lobe epilepsy surgery in adults. A model based upon five variables – side of surgery, sex, education, age at epilepsy onset, and age at epilepsy surgery – performed very well, with a concordance statistic of 0.81. Moreover, a second nomogram predicting moderate to severe postoperative naming decline on the basis of just three variables – side of surgery, age at epilepsy onset, and preoperative score on the Boston Naming Test – had a concordance statistic of 0.84 (Neurology. 2018 Dec 4;91[23]:e2144-e2152. doi: 10.1212/WNL.0000000000006629).
“Our future hopefully is one where there will always be room for gut feelings and intuition because we definitely need them. We want to honor them. But hopefully it is one where algorithms can help our guesses be more educated and where the science of algorithms and predictive modeling can help inform our outcome predictions and decision-making process,” she said.
The original Epilepsy Surgery Nomogram project was funded by the Cleveland Clinic Epilepsy Center. The postoperative naming decline nomograms project was funded by the NIH.
BANGKOK –
She and her colleagues have created and validated an online risk prediction tool that clinicians can use to predict a patient’s individualized likelihood of complete freedom from seizures 2 and 5 years after undergoing resective brain surgery for drug-resistant epilepsy. The risk predictor, known as the Epilepsy Surgery Nomogram, uses a handful of simple clinical characteristics – patient gender, pathologic cause of the seizures, the proposed type of epilepsy surgery, the presence or absence of generalized tonic-clonic seizures, epilepsy duration, and preoperative seizure frequency – and spits out the patient’s predicted seizure outcome, she explained at the congress, sponsored by the International League Against Epilepsy.
“The point here is that every patient is an individual. And to give people predictions based on 500- or 600-patient Kaplan-Meier-derived curves that just provide the average outcome for the whole cohort isn’t really going to give them what they need as far as their individualized chance of becoming seizure free,” said Dr. Jehi, a neurologist at the Cleveland Clinic.
Similarly, reliance solely upon clinical judgment is a minefield. Multiple biases prevent physicians from making objective medical predictions, she continued.
“We think of the process of medical decision-making and outcome prediction as being a process that is logical and rational, where the accumulation of knowledge improves the decisions that we make, and where past experience improves judgment, and where collective decisions are more reliable. This is what intuitively we all think. That’s why we think we are invincible as physicians. And to that I say, really? There is a wealth of literature that actually disproves each one of these points,” Dr. Jehi declared.
Outcomes of brain surgery for drug-resistant epilepsy have remained static for more than half a century: Ten years after surgery, roughly half of treated patients remain completely seizure free. The inability of clinicians to use advanced statistics to inform potential surgical candidates about their individualized chance of becoming seizure free has probably contributed to underutilization of epilepsy surgery, she added.
The Epilepsy Surgery Nomogram was developed through detailed analysis of the records of 846 patients who underwent epilepsy surgery at the Cleveland Clinic. The resultant nomogram was then validated in a cohort of 604 patients who had resective surgery at the Mayo Clinic and epilepsy surgery centers in Brazil, Italy, and France. In the development cohort, the rate of complete freedom from seizures was 57% at 2 years and 40% at 5 years. In the validation study, the nomogram had a concordance statistic of 0.60 for complete freedom from seizures, which is considered better than chance, but well below the 0.80 threshold defined as strong concordance (Lancet Neurol. 2015 Mar;14[3]:283-90).
However, in an era when personalized medicine has become a catch phrase, the Epilepsy Surgery Nomogram has captured the attention of officials at the National Institutes of Health. Indeed, Dr. Jehi and her coworkers have received a $3.4 million, 5-year grant from the NIH to improve their risk prediction model by incorporating additional variables, including EEG data, MRI findings, family history, and genetic information. The enhanced risk calculator also will include a predictor of the likelihood that an individual will experience clinically meaningful improvement in quality of life in response to epilepsy surgery, since that’s an important outcome even in the absence of 100% freedom from seizures.
Recently, Dr. Jehi and coworkers have developed and then externally validated nomograms to predict the individualized risk of clinically relevant postoperative naming decline after temporal lobe epilepsy surgery in adults. A model based upon five variables – side of surgery, sex, education, age at epilepsy onset, and age at epilepsy surgery – performed very well, with a concordance statistic of 0.81. Moreover, a second nomogram predicting moderate to severe postoperative naming decline on the basis of just three variables – side of surgery, age at epilepsy onset, and preoperative score on the Boston Naming Test – had a concordance statistic of 0.84 (Neurology. 2018 Dec 4;91[23]:e2144-e2152. doi: 10.1212/WNL.0000000000006629).
“Our future hopefully is one where there will always be room for gut feelings and intuition because we definitely need them. We want to honor them. But hopefully it is one where algorithms can help our guesses be more educated and where the science of algorithms and predictive modeling can help inform our outcome predictions and decision-making process,” she said.
The original Epilepsy Surgery Nomogram project was funded by the Cleveland Clinic Epilepsy Center. The postoperative naming decline nomograms project was funded by the NIH.
BANGKOK –
She and her colleagues have created and validated an online risk prediction tool that clinicians can use to predict a patient’s individualized likelihood of complete freedom from seizures 2 and 5 years after undergoing resective brain surgery for drug-resistant epilepsy. The risk predictor, known as the Epilepsy Surgery Nomogram, uses a handful of simple clinical characteristics – patient gender, pathologic cause of the seizures, the proposed type of epilepsy surgery, the presence or absence of generalized tonic-clonic seizures, epilepsy duration, and preoperative seizure frequency – and spits out the patient’s predicted seizure outcome, she explained at the congress, sponsored by the International League Against Epilepsy.
“The point here is that every patient is an individual. And to give people predictions based on 500- or 600-patient Kaplan-Meier-derived curves that just provide the average outcome for the whole cohort isn’t really going to give them what they need as far as their individualized chance of becoming seizure free,” said Dr. Jehi, a neurologist at the Cleveland Clinic.
Similarly, reliance solely upon clinical judgment is a minefield. Multiple biases prevent physicians from making objective medical predictions, she continued.
“We think of the process of medical decision-making and outcome prediction as being a process that is logical and rational, where the accumulation of knowledge improves the decisions that we make, and where past experience improves judgment, and where collective decisions are more reliable. This is what intuitively we all think. That’s why we think we are invincible as physicians. And to that I say, really? There is a wealth of literature that actually disproves each one of these points,” Dr. Jehi declared.
Outcomes of brain surgery for drug-resistant epilepsy have remained static for more than half a century: Ten years after surgery, roughly half of treated patients remain completely seizure free. The inability of clinicians to use advanced statistics to inform potential surgical candidates about their individualized chance of becoming seizure free has probably contributed to underutilization of epilepsy surgery, she added.
The Epilepsy Surgery Nomogram was developed through detailed analysis of the records of 846 patients who underwent epilepsy surgery at the Cleveland Clinic. The resultant nomogram was then validated in a cohort of 604 patients who had resective surgery at the Mayo Clinic and epilepsy surgery centers in Brazil, Italy, and France. In the development cohort, the rate of complete freedom from seizures was 57% at 2 years and 40% at 5 years. In the validation study, the nomogram had a concordance statistic of 0.60 for complete freedom from seizures, which is considered better than chance, but well below the 0.80 threshold defined as strong concordance (Lancet Neurol. 2015 Mar;14[3]:283-90).
However, in an era when personalized medicine has become a catch phrase, the Epilepsy Surgery Nomogram has captured the attention of officials at the National Institutes of Health. Indeed, Dr. Jehi and her coworkers have received a $3.4 million, 5-year grant from the NIH to improve their risk prediction model by incorporating additional variables, including EEG data, MRI findings, family history, and genetic information. The enhanced risk calculator also will include a predictor of the likelihood that an individual will experience clinically meaningful improvement in quality of life in response to epilepsy surgery, since that’s an important outcome even in the absence of 100% freedom from seizures.
Recently, Dr. Jehi and coworkers have developed and then externally validated nomograms to predict the individualized risk of clinically relevant postoperative naming decline after temporal lobe epilepsy surgery in adults. A model based upon five variables – side of surgery, sex, education, age at epilepsy onset, and age at epilepsy surgery – performed very well, with a concordance statistic of 0.81. Moreover, a second nomogram predicting moderate to severe postoperative naming decline on the basis of just three variables – side of surgery, age at epilepsy onset, and preoperative score on the Boston Naming Test – had a concordance statistic of 0.84 (Neurology. 2018 Dec 4;91[23]:e2144-e2152. doi: 10.1212/WNL.0000000000006629).
“Our future hopefully is one where there will always be room for gut feelings and intuition because we definitely need them. We want to honor them. But hopefully it is one where algorithms can help our guesses be more educated and where the science of algorithms and predictive modeling can help inform our outcome predictions and decision-making process,” she said.
The original Epilepsy Surgery Nomogram project was funded by the Cleveland Clinic Epilepsy Center. The postoperative naming decline nomograms project was funded by the NIH.
REPORTING FROM IEC 2019
Signals of gut microbiome interaction with experimental Alzheimer’s drug prompt new trial
LOS ANGELES – A single look at the gut microbiome of patients with Alzheimer’s disease (AD) suggests an interaction between anti-inflammatory gut bacteria and long-term exposure to an investigational sigma 1 receptor agonist.
After up to 148 weeks treatment with Anavex 2-73, patients with stable or improved functional scores showed significantly higher levels of both Ruminococcaceae and Porphyromonadaceae, compared with patients who had declining function. Both bacterial families produce butyrate, an anti-inflammatory short-chain fatty acid.
Conversely, poor response was associated with a low level of Verrucomicrobia, a mucin-degrading phylum thought to be important in gut homeostasis. These bacteria live mainly in the intestinal mucosa – the physical interface between the microbiome and the rest of the body.
The data, presented at the Alzheimer’s Association International Conference, represent the first microbiome measurements reported in a clinical trial of an investigational Alzheimer’s therapy. Because they come from a single sample taken from a small group in an extension study, without a baseline comparator, it’s impossible to know what these associations mean. But the findings are enough to nudge Anavex Life Sciences into adding microbiome changes to its new study of Anavex 2-73, according to Christopher Missling, PhD, president and chief executive officer of the company.
The study, ramping up now, aims to recruit 450 patients with mild AD. They will be randomized to high-dose or mid-dose Anavex 2-73 for 48 weeks. The primary outcomes are measures of cognition and function. Stool sampling at baseline and at the end of the study will be included as well, Dr. Missling said in an interview.
Anavex 2-73 is a sigma-1 receptor agonist. A chaperone protein, sigma-1 is activated in response to acute and chronic cellular stressors, several which are important in neurodegeneration. The sigma-1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates several processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. It also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
Anavex 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients. This was followed by a 52-week, open-label extension trial of 10, 20, 30, and 50 mg/day orally, in which each patient was titrated to the maximum tolerated dose. The main endpoints were change on the Mini Mental State Exam and change on the Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL) scale.
At 57 weeks, six patients had improved on the Mini Mental State Exam score: four with high plasma levels and two with low plasma levels, correlating to the dosage obtained. On the functional measure of activities of daily living, nine patients had improved, including five with high plasma levels, three with moderate levels, and one with a low level. One patient, with a moderate level, remained stable. The remaining 14 patients declined.
The company then enrolled 21 of the cohort in a 208-week extension trial, primarily because of patient request, Dr. Missling said. “They know they are doing better. Their families know they’re doing better. They did not want to give this up.”
Last fall, the company released 148-week functional and cognitive data confirming the initial findings: Patients with higher plasma levels (correlating with higher doses) declined about 2 points on the ADCS-ADL scale, compared with a mean decline of about 25 points among those with lower blood levels – an 88% difference in favor of treatment. Cognition scores showed a similar pattern, with the high-concentration group declining 64% less than the low-concentration group.
Sixteen patients consented to stool sampling. A sophisticated computer algorithm characterized the microbiome of each, measuring the relative abundance of phyla. Microbiome analysis wasn’t included as an endpoint in the original study design because, at that time, the idea of a connection between AD and the gut microbiome was barely on the research radar.
Things shifted dramatically in 2017, with a seminal paper finding that germ-free mice inoculated with stool from Parkinson’s patients developed Parkinson’s symptoms. This study was widely heralded as a breakthrough in the field – the first time any neurodegenerative disease had been conclusively linked to dysregulations in the human microbiome.
Last year, Vo Van Giau, PhD, of Gachon University, South Korea, and his colleagues published an extensive review of the data suggesting a similar link with Alzheimer’s disease.
Dr. Giau and his coauthors laid out a potential pathogenic pathway for this interaction.
“The microbiota is closely related to neurological dysfunction and plays a significant role in neuroinflammation through the secretion of proinflammatory cytokines. Changes in the homeostatic state of the microbiota lead to increased intestinal permeability, which may promote the translocation of bacteria and endotoxins across the epithelial barrier, inducing an immunological response associated with the production of proinflammatory cytokines. The activation of both enteric neurons and glial cells may result in various neurological disorders,” including Alzheimer’s, he wrote.
Dr. Missling said this paper, and smaller studies appearing at Alzheimer’s meetings, prompted the company to add the stool sampling as a follow-up measure.
“It’s something of great interest, we think, and deserves to be investigated.”
SOURCE: Missling C et al. AAIC 2019, Abstract 32260.
LOS ANGELES – A single look at the gut microbiome of patients with Alzheimer’s disease (AD) suggests an interaction between anti-inflammatory gut bacteria and long-term exposure to an investigational sigma 1 receptor agonist.
After up to 148 weeks treatment with Anavex 2-73, patients with stable or improved functional scores showed significantly higher levels of both Ruminococcaceae and Porphyromonadaceae, compared with patients who had declining function. Both bacterial families produce butyrate, an anti-inflammatory short-chain fatty acid.
Conversely, poor response was associated with a low level of Verrucomicrobia, a mucin-degrading phylum thought to be important in gut homeostasis. These bacteria live mainly in the intestinal mucosa – the physical interface between the microbiome and the rest of the body.
The data, presented at the Alzheimer’s Association International Conference, represent the first microbiome measurements reported in a clinical trial of an investigational Alzheimer’s therapy. Because they come from a single sample taken from a small group in an extension study, without a baseline comparator, it’s impossible to know what these associations mean. But the findings are enough to nudge Anavex Life Sciences into adding microbiome changes to its new study of Anavex 2-73, according to Christopher Missling, PhD, president and chief executive officer of the company.
The study, ramping up now, aims to recruit 450 patients with mild AD. They will be randomized to high-dose or mid-dose Anavex 2-73 for 48 weeks. The primary outcomes are measures of cognition and function. Stool sampling at baseline and at the end of the study will be included as well, Dr. Missling said in an interview.
Anavex 2-73 is a sigma-1 receptor agonist. A chaperone protein, sigma-1 is activated in response to acute and chronic cellular stressors, several which are important in neurodegeneration. The sigma-1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates several processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. It also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
Anavex 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients. This was followed by a 52-week, open-label extension trial of 10, 20, 30, and 50 mg/day orally, in which each patient was titrated to the maximum tolerated dose. The main endpoints were change on the Mini Mental State Exam and change on the Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL) scale.
At 57 weeks, six patients had improved on the Mini Mental State Exam score: four with high plasma levels and two with low plasma levels, correlating to the dosage obtained. On the functional measure of activities of daily living, nine patients had improved, including five with high plasma levels, three with moderate levels, and one with a low level. One patient, with a moderate level, remained stable. The remaining 14 patients declined.
The company then enrolled 21 of the cohort in a 208-week extension trial, primarily because of patient request, Dr. Missling said. “They know they are doing better. Their families know they’re doing better. They did not want to give this up.”
Last fall, the company released 148-week functional and cognitive data confirming the initial findings: Patients with higher plasma levels (correlating with higher doses) declined about 2 points on the ADCS-ADL scale, compared with a mean decline of about 25 points among those with lower blood levels – an 88% difference in favor of treatment. Cognition scores showed a similar pattern, with the high-concentration group declining 64% less than the low-concentration group.
Sixteen patients consented to stool sampling. A sophisticated computer algorithm characterized the microbiome of each, measuring the relative abundance of phyla. Microbiome analysis wasn’t included as an endpoint in the original study design because, at that time, the idea of a connection between AD and the gut microbiome was barely on the research radar.
Things shifted dramatically in 2017, with a seminal paper finding that germ-free mice inoculated with stool from Parkinson’s patients developed Parkinson’s symptoms. This study was widely heralded as a breakthrough in the field – the first time any neurodegenerative disease had been conclusively linked to dysregulations in the human microbiome.
Last year, Vo Van Giau, PhD, of Gachon University, South Korea, and his colleagues published an extensive review of the data suggesting a similar link with Alzheimer’s disease.
Dr. Giau and his coauthors laid out a potential pathogenic pathway for this interaction.
“The microbiota is closely related to neurological dysfunction and plays a significant role in neuroinflammation through the secretion of proinflammatory cytokines. Changes in the homeostatic state of the microbiota lead to increased intestinal permeability, which may promote the translocation of bacteria and endotoxins across the epithelial barrier, inducing an immunological response associated with the production of proinflammatory cytokines. The activation of both enteric neurons and glial cells may result in various neurological disorders,” including Alzheimer’s, he wrote.
Dr. Missling said this paper, and smaller studies appearing at Alzheimer’s meetings, prompted the company to add the stool sampling as a follow-up measure.
“It’s something of great interest, we think, and deserves to be investigated.”
SOURCE: Missling C et al. AAIC 2019, Abstract 32260.
LOS ANGELES – A single look at the gut microbiome of patients with Alzheimer’s disease (AD) suggests an interaction between anti-inflammatory gut bacteria and long-term exposure to an investigational sigma 1 receptor agonist.
After up to 148 weeks treatment with Anavex 2-73, patients with stable or improved functional scores showed significantly higher levels of both Ruminococcaceae and Porphyromonadaceae, compared with patients who had declining function. Both bacterial families produce butyrate, an anti-inflammatory short-chain fatty acid.
Conversely, poor response was associated with a low level of Verrucomicrobia, a mucin-degrading phylum thought to be important in gut homeostasis. These bacteria live mainly in the intestinal mucosa – the physical interface between the microbiome and the rest of the body.
The data, presented at the Alzheimer’s Association International Conference, represent the first microbiome measurements reported in a clinical trial of an investigational Alzheimer’s therapy. Because they come from a single sample taken from a small group in an extension study, without a baseline comparator, it’s impossible to know what these associations mean. But the findings are enough to nudge Anavex Life Sciences into adding microbiome changes to its new study of Anavex 2-73, according to Christopher Missling, PhD, president and chief executive officer of the company.
The study, ramping up now, aims to recruit 450 patients with mild AD. They will be randomized to high-dose or mid-dose Anavex 2-73 for 48 weeks. The primary outcomes are measures of cognition and function. Stool sampling at baseline and at the end of the study will be included as well, Dr. Missling said in an interview.
Anavex 2-73 is a sigma-1 receptor agonist. A chaperone protein, sigma-1 is activated in response to acute and chronic cellular stressors, several which are important in neurodegeneration. The sigma-1 receptor is found on neurons and glia in many areas of the central nervous system. It modulates several processes implicated in neurodegenerative diseases, including glutamate and calcium activity, reaction to oxidative stress, and mitochondrial function. There is some evidence that sigma-1 receptor activation can induce neuronal regrowth and functional recovery after stroke. It also appears to play a role in helping cells clear misfolded proteins – a pathway that makes it an attractive drug target in Alzheimer’s disease, as well as other neurodegenerative diseases with aberrant proteins, such as Parkinson’s and Huntington’s diseases.
Anavex 2-73’s phase 2 development started with a 5-week crossover trial of 32 patients. This was followed by a 52-week, open-label extension trial of 10, 20, 30, and 50 mg/day orally, in which each patient was titrated to the maximum tolerated dose. The main endpoints were change on the Mini Mental State Exam and change on the Alzheimer’s Disease Cooperative Study-activities of daily living (ADCS-ADL) scale.
At 57 weeks, six patients had improved on the Mini Mental State Exam score: four with high plasma levels and two with low plasma levels, correlating to the dosage obtained. On the functional measure of activities of daily living, nine patients had improved, including five with high plasma levels, three with moderate levels, and one with a low level. One patient, with a moderate level, remained stable. The remaining 14 patients declined.
The company then enrolled 21 of the cohort in a 208-week extension trial, primarily because of patient request, Dr. Missling said. “They know they are doing better. Their families know they’re doing better. They did not want to give this up.”
Last fall, the company released 148-week functional and cognitive data confirming the initial findings: Patients with higher plasma levels (correlating with higher doses) declined about 2 points on the ADCS-ADL scale, compared with a mean decline of about 25 points among those with lower blood levels – an 88% difference in favor of treatment. Cognition scores showed a similar pattern, with the high-concentration group declining 64% less than the low-concentration group.
Sixteen patients consented to stool sampling. A sophisticated computer algorithm characterized the microbiome of each, measuring the relative abundance of phyla. Microbiome analysis wasn’t included as an endpoint in the original study design because, at that time, the idea of a connection between AD and the gut microbiome was barely on the research radar.
Things shifted dramatically in 2017, with a seminal paper finding that germ-free mice inoculated with stool from Parkinson’s patients developed Parkinson’s symptoms. This study was widely heralded as a breakthrough in the field – the first time any neurodegenerative disease had been conclusively linked to dysregulations in the human microbiome.
Last year, Vo Van Giau, PhD, of Gachon University, South Korea, and his colleagues published an extensive review of the data suggesting a similar link with Alzheimer’s disease.
Dr. Giau and his coauthors laid out a potential pathogenic pathway for this interaction.
“The microbiota is closely related to neurological dysfunction and plays a significant role in neuroinflammation through the secretion of proinflammatory cytokines. Changes in the homeostatic state of the microbiota lead to increased intestinal permeability, which may promote the translocation of bacteria and endotoxins across the epithelial barrier, inducing an immunological response associated with the production of proinflammatory cytokines. The activation of both enteric neurons and glial cells may result in various neurological disorders,” including Alzheimer’s, he wrote.
Dr. Missling said this paper, and smaller studies appearing at Alzheimer’s meetings, prompted the company to add the stool sampling as a follow-up measure.
“It’s something of great interest, we think, and deserves to be investigated.”
SOURCE: Missling C et al. AAIC 2019, Abstract 32260.
REPORTING FROM AAIC 2019
Sleep disorder treatment tied to lower suicide attempt risk in veterans
in a large case-control matched study of patients in the Veterans Health Administration database.
However, treatment for sleep disorders was correlated to a reduced risk for suicide attempts.
Todd M. Bishop, PhD, of the Center of Excellence for Suicide Prevention, Canandaigua (N.Y.) VA Medical Center, and the department of psychiatry, University of Rochester (N.Y.) Medical Center, and his colleagues wrote that suicide is the 10th most frequent cause of death in the United States, and “nowhere is the suicide rate more alarming than among military veterans, who after adjusting for age and gender, have an approximately 1.5 times greater risk for suicide as compared to the civilian population.”
Previous research has explored the link between sleep disturbances and suicide attempts. But less has been done to look at specific sleep problems, and little research has examined the role of sleep medicine interventions and suicide attempt risk.
The investigators conducted a study to establish the association between suicide attempts and specific sleep disorders, and to examine the correlation between sleep medicine treatment and suicide attempts. Their sample consisted of 60,102 veterans who had received care within the VHA between Oct. 1, 2012, and Sept. 20, 2014. Half of the sample had a documented suicide attempt in the medical record (n = 30,051) and half did not (n = 30,051). The overall sample was predominately male (87.1%) with a mean age of 48.6 years. More than half the sample identified as white (67.4%).
Suicide attempts, sleep disturbance, and medical and mental health comorbidities were identified via ICD codes and prescription records. The predominant sleep disorders studied were insomnia, sleep-related breathing disorder (SRBD), and nightmares. The first suicide attempt in the study period was determined to be the index date for the case-control matching.
Overall, sleep disturbances were much more prevalent among cases than controls (insomnia, 46.2% vs. 12.6%), sleep-related breathing disorder (8.6% vs. 4.8%), and nightmares (7.1% vs. 1.6%). A logistic regression analysis was undertaken to examine the relationship between specific sleep disorders and suicide attempts. Insomnia, nightmares, and SRBD were each associated with increased odds of a suicide attempt with the following odds ratios: insomnia (odds ratio, 5.62; 95% confidence interval, 5.39-5.86), nightmares (OR, 2.49; 95% CI, 2.23-2.77), and sleep-related breathing disorder (OR, 1.37; 95% CI, 1.27-1.48).
A second model included known drivers of suicide attempts (PTSD, depression, anxiety disorders, schizophrenia, bipolar disorder, substance use disorder, medical comorbidity, and obesity). But after controlling for these factors, neither nightmares (OR, 0.96; 95% CI, 0.85-1.09) nor sleep-related breathing disorders (OR, 0.87, 95% CI, 0.79-0.94) remained positively associated with suicide attempt, but the association of insomnia with suicide attempt was maintained (OR, 1.51; 95% CI, 1.43-1.59).
The question of the impact of sleep medicine interventions on suicide attempts was studied with a third regression model adding the number of sleep medicine clinic visits in the 180 days prior to the suicide attempt index date as an independent variable. The variables in this model were limited to insomnia, SRBD, and nightmares. The investigators found that “for each sleep medicine clinic visit within the 6 months prior to index date the likelihood of suicide attempt is 11% less (OR, 0.89; 95% CI, 0.82-0.97).”
The limitations of the study include the lack of information on sleep treatment modalities or medications provided during the clinic visits, and the overlapping of sleep disturbance with other mental health conditions, such as alcohol dependence and PTSD. In addition, “some insomnia medications are labeled for risk of suicidal ideation and behavior, so there is some chance that the medications rather than insomnia itself were associated with the increased suicidal behavior,” the investigators wrote.
In addition to an analysis of specific types of sleep disorders associated with suicide attempts, the study showed that treatment of sleep disorders may have an important role in suicide prevention. The investigators concluded: “Identifying populations at risk for suicide prior to a first attempt is an important, but difficult task of suicide prevention. Prevention efforts can be aimed at modifiable risk factors that arise early on a patient’s trajectory toward a suicide attempt.”
The study was supported by the VISN 2 Center of Excellence for Suicide Prevention, Canandaigua VAMC. The authors had no disclosures.
SOURCE: Bishop TM et al. Sleep Med. 2019 Jul 25. doi: 10.1016/j.sleep.2019.07.016.
in a large case-control matched study of patients in the Veterans Health Administration database.
However, treatment for sleep disorders was correlated to a reduced risk for suicide attempts.
Todd M. Bishop, PhD, of the Center of Excellence for Suicide Prevention, Canandaigua (N.Y.) VA Medical Center, and the department of psychiatry, University of Rochester (N.Y.) Medical Center, and his colleagues wrote that suicide is the 10th most frequent cause of death in the United States, and “nowhere is the suicide rate more alarming than among military veterans, who after adjusting for age and gender, have an approximately 1.5 times greater risk for suicide as compared to the civilian population.”
Previous research has explored the link between sleep disturbances and suicide attempts. But less has been done to look at specific sleep problems, and little research has examined the role of sleep medicine interventions and suicide attempt risk.
The investigators conducted a study to establish the association between suicide attempts and specific sleep disorders, and to examine the correlation between sleep medicine treatment and suicide attempts. Their sample consisted of 60,102 veterans who had received care within the VHA between Oct. 1, 2012, and Sept. 20, 2014. Half of the sample had a documented suicide attempt in the medical record (n = 30,051) and half did not (n = 30,051). The overall sample was predominately male (87.1%) with a mean age of 48.6 years. More than half the sample identified as white (67.4%).
Suicide attempts, sleep disturbance, and medical and mental health comorbidities were identified via ICD codes and prescription records. The predominant sleep disorders studied were insomnia, sleep-related breathing disorder (SRBD), and nightmares. The first suicide attempt in the study period was determined to be the index date for the case-control matching.
Overall, sleep disturbances were much more prevalent among cases than controls (insomnia, 46.2% vs. 12.6%), sleep-related breathing disorder (8.6% vs. 4.8%), and nightmares (7.1% vs. 1.6%). A logistic regression analysis was undertaken to examine the relationship between specific sleep disorders and suicide attempts. Insomnia, nightmares, and SRBD were each associated with increased odds of a suicide attempt with the following odds ratios: insomnia (odds ratio, 5.62; 95% confidence interval, 5.39-5.86), nightmares (OR, 2.49; 95% CI, 2.23-2.77), and sleep-related breathing disorder (OR, 1.37; 95% CI, 1.27-1.48).
A second model included known drivers of suicide attempts (PTSD, depression, anxiety disorders, schizophrenia, bipolar disorder, substance use disorder, medical comorbidity, and obesity). But after controlling for these factors, neither nightmares (OR, 0.96; 95% CI, 0.85-1.09) nor sleep-related breathing disorders (OR, 0.87, 95% CI, 0.79-0.94) remained positively associated with suicide attempt, but the association of insomnia with suicide attempt was maintained (OR, 1.51; 95% CI, 1.43-1.59).
The question of the impact of sleep medicine interventions on suicide attempts was studied with a third regression model adding the number of sleep medicine clinic visits in the 180 days prior to the suicide attempt index date as an independent variable. The variables in this model were limited to insomnia, SRBD, and nightmares. The investigators found that “for each sleep medicine clinic visit within the 6 months prior to index date the likelihood of suicide attempt is 11% less (OR, 0.89; 95% CI, 0.82-0.97).”
The limitations of the study include the lack of information on sleep treatment modalities or medications provided during the clinic visits, and the overlapping of sleep disturbance with other mental health conditions, such as alcohol dependence and PTSD. In addition, “some insomnia medications are labeled for risk of suicidal ideation and behavior, so there is some chance that the medications rather than insomnia itself were associated with the increased suicidal behavior,” the investigators wrote.
In addition to an analysis of specific types of sleep disorders associated with suicide attempts, the study showed that treatment of sleep disorders may have an important role in suicide prevention. The investigators concluded: “Identifying populations at risk for suicide prior to a first attempt is an important, but difficult task of suicide prevention. Prevention efforts can be aimed at modifiable risk factors that arise early on a patient’s trajectory toward a suicide attempt.”
The study was supported by the VISN 2 Center of Excellence for Suicide Prevention, Canandaigua VAMC. The authors had no disclosures.
SOURCE: Bishop TM et al. Sleep Med. 2019 Jul 25. doi: 10.1016/j.sleep.2019.07.016.
in a large case-control matched study of patients in the Veterans Health Administration database.
However, treatment for sleep disorders was correlated to a reduced risk for suicide attempts.
Todd M. Bishop, PhD, of the Center of Excellence for Suicide Prevention, Canandaigua (N.Y.) VA Medical Center, and the department of psychiatry, University of Rochester (N.Y.) Medical Center, and his colleagues wrote that suicide is the 10th most frequent cause of death in the United States, and “nowhere is the suicide rate more alarming than among military veterans, who after adjusting for age and gender, have an approximately 1.5 times greater risk for suicide as compared to the civilian population.”
Previous research has explored the link between sleep disturbances and suicide attempts. But less has been done to look at specific sleep problems, and little research has examined the role of sleep medicine interventions and suicide attempt risk.
The investigators conducted a study to establish the association between suicide attempts and specific sleep disorders, and to examine the correlation between sleep medicine treatment and suicide attempts. Their sample consisted of 60,102 veterans who had received care within the VHA between Oct. 1, 2012, and Sept. 20, 2014. Half of the sample had a documented suicide attempt in the medical record (n = 30,051) and half did not (n = 30,051). The overall sample was predominately male (87.1%) with a mean age of 48.6 years. More than half the sample identified as white (67.4%).
Suicide attempts, sleep disturbance, and medical and mental health comorbidities were identified via ICD codes and prescription records. The predominant sleep disorders studied were insomnia, sleep-related breathing disorder (SRBD), and nightmares. The first suicide attempt in the study period was determined to be the index date for the case-control matching.
Overall, sleep disturbances were much more prevalent among cases than controls (insomnia, 46.2% vs. 12.6%), sleep-related breathing disorder (8.6% vs. 4.8%), and nightmares (7.1% vs. 1.6%). A logistic regression analysis was undertaken to examine the relationship between specific sleep disorders and suicide attempts. Insomnia, nightmares, and SRBD were each associated with increased odds of a suicide attempt with the following odds ratios: insomnia (odds ratio, 5.62; 95% confidence interval, 5.39-5.86), nightmares (OR, 2.49; 95% CI, 2.23-2.77), and sleep-related breathing disorder (OR, 1.37; 95% CI, 1.27-1.48).
A second model included known drivers of suicide attempts (PTSD, depression, anxiety disorders, schizophrenia, bipolar disorder, substance use disorder, medical comorbidity, and obesity). But after controlling for these factors, neither nightmares (OR, 0.96; 95% CI, 0.85-1.09) nor sleep-related breathing disorders (OR, 0.87, 95% CI, 0.79-0.94) remained positively associated with suicide attempt, but the association of insomnia with suicide attempt was maintained (OR, 1.51; 95% CI, 1.43-1.59).
The question of the impact of sleep medicine interventions on suicide attempts was studied with a third regression model adding the number of sleep medicine clinic visits in the 180 days prior to the suicide attempt index date as an independent variable. The variables in this model were limited to insomnia, SRBD, and nightmares. The investigators found that “for each sleep medicine clinic visit within the 6 months prior to index date the likelihood of suicide attempt is 11% less (OR, 0.89; 95% CI, 0.82-0.97).”
The limitations of the study include the lack of information on sleep treatment modalities or medications provided during the clinic visits, and the overlapping of sleep disturbance with other mental health conditions, such as alcohol dependence and PTSD. In addition, “some insomnia medications are labeled for risk of suicidal ideation and behavior, so there is some chance that the medications rather than insomnia itself were associated with the increased suicidal behavior,” the investigators wrote.
In addition to an analysis of specific types of sleep disorders associated with suicide attempts, the study showed that treatment of sleep disorders may have an important role in suicide prevention. The investigators concluded: “Identifying populations at risk for suicide prior to a first attempt is an important, but difficult task of suicide prevention. Prevention efforts can be aimed at modifiable risk factors that arise early on a patient’s trajectory toward a suicide attempt.”
The study was supported by the VISN 2 Center of Excellence for Suicide Prevention, Canandaigua VAMC. The authors had no disclosures.
SOURCE: Bishop TM et al. Sleep Med. 2019 Jul 25. doi: 10.1016/j.sleep.2019.07.016.
REPORTING FROM SLEEP MEDICINE