Neurology

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

[email protected]

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

[email protected]

The Food and Drug Administration has granted accelerated approval to Vyondys 53 (golodirsen) to treat patients with Duchenne muscular dystrophy (DMD) who have a mutation of the dystrophin gene that is amenable to exon 53 skipping. About 8% of patients with DMD have this type of mutation. Further research is required to establish whether the antisense oligonucleotide provides clinical benefit, the agency said.

Separately, the agency approved the first newborn screening test for DMD.

DMD is a “rare and devastating disease,” said Billy Dunn, MD, acting director of the office of neuroscience in the FDA’s Center for Drug Evaluation and Research.

“Patients ... who have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” Dr. Dunn said in a news release. “Use of the accelerated approval pathway will make Vyondys 53 available to patients based on initial data, and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”
 

A surrogate endpoint

The FDA approved Vyondys 53 based on the surrogate endpoint of increased dystrophin production in the skeletal muscle in some patients treated with the drug. Sarepta Therapeutics, the developer of Vyondys 53, evaluated the treatment in a two-part clinical study. In the first part, eight patients with DMD received Vyondys 53, and four received placebo. In the second part, 25 patients, including the 12 patients from the first part, received open-label treatment. Dystrophin levels increased from 0.10% of normal at baseline to 1.02% of normal after at least 48 weeks of treatment.

A placebo-controlled, confirmatory trial is expected to conclude by 2024, the company said. If the trial does not confirm clinical benefit, the FDA could withdraw approval of the drug.

The most common side effects in patients who received Vyondys 53 include headache, fever, fall, cough, vomiting, abdominal pain, cold symptoms, and nausea. Some patients had hypersensitivity reactions. Renal toxicity occurred in animal studies of golodirsen, but not in the clinical studies. Renal toxicity, however, has occurred after treatment with other antisense oligonucleotides, the FDA noted.

Sarepta said Vyondys 53, an injection, would be available immediately. The drug is the company’s second RNA exon-skipping treatment for DMD. The FDA approved the first treatment, Exondys 51 (eteplirsen), in 2016. Together, the two drugs can treat about 20% of patients with DMD, the company said.
 

Newborn screening

On the same day, Dec. 12, 2019, the FDA authorized marketing of the first test to aid in newborn screening for DMD. Although authorization for the GSP Neonatal Creatine Kinase–MM kit enables laboratories to add this test to their newborn screening panel, it “does not signal a recommendation for DMD to be added ... as a condition for which newborn screening is recommended,” the agency said. In addition, the FDA noted that the kit is not meant to diagnose DMD or to screen for other muscular dystrophies.

The GSP Neonatal Creatine Kinase–MM kit measures the concentration of CK-MM, a type of protein that increases when there is muscle damage. The test measures CK-MM in dried blood samples collected from a newborn’s heel 24-48 hours after birth. Elevated levels may indicate DMD, but physicians must confirm the diagnosis using other methods, such as muscle biopsies, genetic testing, and other laboratory tests.

DMD primarily affects boys, and patients often do not have a family history of the condition. About 1 in 3,600 male live-born infants worldwide have DMD. Symptom onset usually occurs between the ages of 3 and 5 years.

The FDA reviewed the kit through the de novo premarket review pathway for low to moderate risk devices. In a clinical study of 3,041 newborns, the kit identified the four screened newborns who had DMD-causing genetic mutations. In addition, the test correctly identified 30 samples from newborns with clinically confirmed cases of DMD.

PerkinElmer developed the GSP Neonatal Creatine Kinase–MM kit.
 

[email protected]

SAN DIEGO – To prevent dementia, follow Mom’s advice: Get up off the couch, go play with your friends, and eat your vegetables.

Michele G. Sullivan/MDedge News

After 15 years of disappointing drug trials, strong new evidence says the best way to attack Alzheimer’s disease is not to treat it once it develops, but to prevent it in the first place, Laura D. Baker, PhD, said at the Clinical Trials on Alzheimer’s Disease conference. Studies of exercise, cognitive and social stimulation, and diet show that each one can reduce the risk of dementia, and that a combination of all three may have even a more powerful and synergistic effect.

“We have become absolutely phobic of exercise,” said Dr. Baker of Wake Forest University, Winston-Salem, N.C. And it’s not just structured exercise we shirk. “We take the closest parking space, sit for hours on end, don’t even take the stairs. Yet we know from years of work that exercise has a powerful benefit on cardiovascular disease, lipid profiles, metabolic disease, stress, and mood. Now we are seeing that exercise also promotes brain health in normal aging and protects against cognitive decline and prevention.”
 

Get off the couch

The general benefits of exercise – chiefly aerobic exercise – are myriad, Dr. Baker said.

“Exercise increases effective neurorepair. It reduces oxidative stress. It improves insulin sensitivity and helps with maintaining normal weight. It reduces inflammation and increases normal clearance of amyloid-beta.”

A 2017 meta-analysis reviewed some of these findings. “The current review [of 16 studies] suggests that aerobic exercise may have positive effects on the right hippocampus and potentially beneficial effects on the overall and other parts of the hippocampus, the cingulate cortex, and the medial temporal areas. ... Moreover, aerobic exercise may increase functional connectivity or activation in the hippocampus, cingulate cortex, and parahippocampal gyrus regions,” wrote Mo-yi Li, PhD, of Fujian University of Traditional Chinese Medicine, Fuzhou, China, and colleagues.

Exercise increases brain-derived neurotrophic factor (BDNF), which in turn increases neuronal potentiation and synaptic plasticity. BDNF is also important in hippocampal neurogenesis; mice, after just one aerobic session, showed dramatic boosts in BDNF. A 2018 review elaborates on these findings.

Eat right

Diet mediates dementia risk through less direct, but very effective, pathways, Dr. Baker said. Diets rich in vegetables, berries, nuts, fish, lean proteins, and healthy fats improves virtually all metabolic measures. These, in turn, reduce the risk cerebrovascular disease – an important driver of vascular dementias and a contributor to Alzheimer’s disease risk as well.

The MIND diet study (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), reported in 2015 was a very successful demonstration of this concept. A combination of the Mediterranean diet and the DASH diet (Dietary Approaches to Stop Hypertension), the MIND diet stresses frequent consumption of vegetables – especially leafy greens – as well as nuts, berries, whole grains, fish, poultry, and wine or grape juice. In the large, nearly 5-year study of 923 subjects aged 58-98 years, the MIND diet was associated with significant gains in cognition – equivalent to a 7-year reversal of age. After 4.5 years, those who strictly adhered to the diet had a 53% reduction in risk for Alzheimer’s disease, and those who adhered moderately had a 35% reduction. And in a more recent Australian longitudinal study, the MIND diet was associated with a 53% reduced risk of cognitive impairment over 12 years.

Ketogenic diets also may exert a benefit. Theoretically, a state of ketosis forces the brain to burn ketones as an alternative fuel to glucose, thus boosting brain function in glucose-starved brains. A small pilot study with exploratory cognitive endpoints determined that diet-compliant subjects with mild to moderate Alzheimer’s experienced a mean 5-point improvement in the Alzheimer’s Disease Assessment Score–Cognition. They reverted to baseline scores within a month of ending the study.

Recent initial work into the gut microbiome provides some additional speculative, but interesting, data. A dysregulated microbiome can shift microbial populations toward a more inflammatory profile. Some work suggests that inflammatory cytokines then travel to the brain and induce a hyperresponse of neuron-damaging immune cells. A comprehensive review article discusses the complicated mechanisms that may be in play.

Play with your friends

Cognitive stimulation and social interaction also appear to modify dementia risk, although the data are a little more limited. But personal interaction is a key element of Dr. Baker’s ongoing EXERT trial.

The ongoing phase 3 trial randomized 300 adults with amnestic mild cognitive impairment to moderate to high intensity aerobic exercise plus one-on-one support at local YMCA gyms or a low-intensity stretching, balance, and range of motion program. In additional to cognitive testing, the trial includes brain imaging, cerebrospinal fluid sampling for biomarkers of Alzheimer’s disease, and a sleep study.

A key component is personal interaction with a trainer. “They spend a lot of one-on-one time with each person,” Dr. Baker said. “For me, that’s the crucial ingredient – that personal touch. It’s what helps people move from Point A to Point B in their behaviors.”

Virtual cognitive stimulation is also a burgeoning area of dementia prevention research right now. Numerous studies are ongoing to test whether virtual reality or other computer-based games might keep the mind sharp or even improve cognition in people at risk.
 

The power of three

If one lifestyle change can reduce dementia risk, what happens when all three work together?

That’s the newest question, first successfully explored in the mid-2000s, with the FINGER study (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability). In FINGER, the triad of exercise, personal support at the gym, and a modified Mediterranean diet reduced Alzheimer’s disease risk and improved cognition relative to the control group.

FINGER showed that the intervention was feasible and that it was associated with cognitive preservation and reduced Alzheimer’s disease risk in a group of at-risk subjects. The active group also had a 25% greater improvement on a neuropsychological test battery relative to the control group. They also performed 150% better in processing speed, 83% better in executive function, and 40% better in short-term memory. They showed no increased risk of cognitive decline relative to the control group, which experienced a 30% increase in risk, according to lead investigator Miia Kivipelto, PhD, of the Karolinska Institute, Stockholm.

So successful was FINGER that it launched a global consortium of related studies called World Wide FINGERS. Active in six countries now, including the United States, the studies aim to discover whether such combinations of lifestyle interventions are workable across countries and cultures. World Wide FINGERS is largely supported by the Alzheimer’s Association.

Global enthusiasm for lifestyle interventions

In recognition of the importance of lifestyle changes for dementia prevention, the World Health Organization recently published “Risk reduction of cognitive decline and dementia.” The document reviews many studies and makes recommendations regarding not only exercise, diet, and cognitive stimulation, but also smoking and alcohol.

Research interest in these areas is surging, Dr. Baker said. “The [U.S.] National Institute on Aging now has 29 ongoing trials. There’s a strong commitment to investigations into how lifestyle interventions could protect brain health as we get older. Certainly, many fit and healthy people do develop Alzheimer’s. But for some, it could be medicine.”

But no matter how compliant people are, lifestyle changes will never completely rid the world of Alzheimer’s and other dementias. The view of Dr. Baker – and most other Alzheimer’s researchers – is to employ lifestyle changes to reduce risk as much as possible and not to stop when cognitive problems do present.

“We need to understand how lifestyle interventions might work in combination with pharmaceuticals,” she said. “If we can support the health of the body and the health of the mind, lifestyle interventions can be the fertilizer that would help drug therapy have its maximum effect.”

[email protected]

SAN DIEGO – To prevent dementia, follow Mom’s advice: Get up off the couch, go play with your friends, and eat your vegetables.

Michele G. Sullivan/MDedge News

After 15 years of disappointing drug trials, strong new evidence says the best way to attack Alzheimer’s disease is not to treat it once it develops, but to prevent it in the first place, Laura D. Baker, PhD, said at the Clinical Trials on Alzheimer’s Disease conference. Studies of exercise, cognitive and social stimulation, and diet show that each one can reduce the risk of dementia, and that a combination of all three may have even a more powerful and synergistic effect.

“We have become absolutely phobic of exercise,” said Dr. Baker of Wake Forest University, Winston-Salem, N.C. And it’s not just structured exercise we shirk. “We take the closest parking space, sit for hours on end, don’t even take the stairs. Yet we know from years of work that exercise has a powerful benefit on cardiovascular disease, lipid profiles, metabolic disease, stress, and mood. Now we are seeing that exercise also promotes brain health in normal aging and protects against cognitive decline and prevention.”
 

Get off the couch

The general benefits of exercise – chiefly aerobic exercise – are myriad, Dr. Baker said.

“Exercise increases effective neurorepair. It reduces oxidative stress. It improves insulin sensitivity and helps with maintaining normal weight. It reduces inflammation and increases normal clearance of amyloid-beta.”

A 2017 meta-analysis reviewed some of these findings. “The current review [of 16 studies] suggests that aerobic exercise may have positive effects on the right hippocampus and potentially beneficial effects on the overall and other parts of the hippocampus, the cingulate cortex, and the medial temporal areas. ... Moreover, aerobic exercise may increase functional connectivity or activation in the hippocampus, cingulate cortex, and parahippocampal gyrus regions,” wrote Mo-yi Li, PhD, of Fujian University of Traditional Chinese Medicine, Fuzhou, China, and colleagues.

Exercise increases brain-derived neurotrophic factor (BDNF), which in turn increases neuronal potentiation and synaptic plasticity. BDNF is also important in hippocampal neurogenesis; mice, after just one aerobic session, showed dramatic boosts in BDNF. A 2018 review elaborates on these findings.

Eat right

Diet mediates dementia risk through less direct, but very effective, pathways, Dr. Baker said. Diets rich in vegetables, berries, nuts, fish, lean proteins, and healthy fats improves virtually all metabolic measures. These, in turn, reduce the risk cerebrovascular disease – an important driver of vascular dementias and a contributor to Alzheimer’s disease risk as well.

The MIND diet study (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), reported in 2015 was a very successful demonstration of this concept. A combination of the Mediterranean diet and the DASH diet (Dietary Approaches to Stop Hypertension), the MIND diet stresses frequent consumption of vegetables – especially leafy greens – as well as nuts, berries, whole grains, fish, poultry, and wine or grape juice. In the large, nearly 5-year study of 923 subjects aged 58-98 years, the MIND diet was associated with significant gains in cognition – equivalent to a 7-year reversal of age. After 4.5 years, those who strictly adhered to the diet had a 53% reduction in risk for Alzheimer’s disease, and those who adhered moderately had a 35% reduction. And in a more recent Australian longitudinal study, the MIND diet was associated with a 53% reduced risk of cognitive impairment over 12 years.

Ketogenic diets also may exert a benefit. Theoretically, a state of ketosis forces the brain to burn ketones as an alternative fuel to glucose, thus boosting brain function in glucose-starved brains. A small pilot study with exploratory cognitive endpoints determined that diet-compliant subjects with mild to moderate Alzheimer’s experienced a mean 5-point improvement in the Alzheimer’s Disease Assessment Score–Cognition. They reverted to baseline scores within a month of ending the study.

Recent initial work into the gut microbiome provides some additional speculative, but interesting, data. A dysregulated microbiome can shift microbial populations toward a more inflammatory profile. Some work suggests that inflammatory cytokines then travel to the brain and induce a hyperresponse of neuron-damaging immune cells. A comprehensive review article discusses the complicated mechanisms that may be in play.

Play with your friends

Cognitive stimulation and social interaction also appear to modify dementia risk, although the data are a little more limited. But personal interaction is a key element of Dr. Baker’s ongoing EXERT trial.

The ongoing phase 3 trial randomized 300 adults with amnestic mild cognitive impairment to moderate to high intensity aerobic exercise plus one-on-one support at local YMCA gyms or a low-intensity stretching, balance, and range of motion program. In additional to cognitive testing, the trial includes brain imaging, cerebrospinal fluid sampling for biomarkers of Alzheimer’s disease, and a sleep study.

A key component is personal interaction with a trainer. “They spend a lot of one-on-one time with each person,” Dr. Baker said. “For me, that’s the crucial ingredient – that personal touch. It’s what helps people move from Point A to Point B in their behaviors.”

Virtual cognitive stimulation is also a burgeoning area of dementia prevention research right now. Numerous studies are ongoing to test whether virtual reality or other computer-based games might keep the mind sharp or even improve cognition in people at risk.
 

The power of three

If one lifestyle change can reduce dementia risk, what happens when all three work together?

That’s the newest question, first successfully explored in the mid-2000s, with the FINGER study (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability). In FINGER, the triad of exercise, personal support at the gym, and a modified Mediterranean diet reduced Alzheimer’s disease risk and improved cognition relative to the control group.

FINGER showed that the intervention was feasible and that it was associated with cognitive preservation and reduced Alzheimer’s disease risk in a group of at-risk subjects. The active group also had a 25% greater improvement on a neuropsychological test battery relative to the control group. They also performed 150% better in processing speed, 83% better in executive function, and 40% better in short-term memory. They showed no increased risk of cognitive decline relative to the control group, which experienced a 30% increase in risk, according to lead investigator Miia Kivipelto, PhD, of the Karolinska Institute, Stockholm.

So successful was FINGER that it launched a global consortium of related studies called World Wide FINGERS. Active in six countries now, including the United States, the studies aim to discover whether such combinations of lifestyle interventions are workable across countries and cultures. World Wide FINGERS is largely supported by the Alzheimer’s Association.

Global enthusiasm for lifestyle interventions

In recognition of the importance of lifestyle changes for dementia prevention, the World Health Organization recently published “Risk reduction of cognitive decline and dementia.” The document reviews many studies and makes recommendations regarding not only exercise, diet, and cognitive stimulation, but also smoking and alcohol.

Research interest in these areas is surging, Dr. Baker said. “The [U.S.] National Institute on Aging now has 29 ongoing trials. There’s a strong commitment to investigations into how lifestyle interventions could protect brain health as we get older. Certainly, many fit and healthy people do develop Alzheimer’s. But for some, it could be medicine.”

But no matter how compliant people are, lifestyle changes will never completely rid the world of Alzheimer’s and other dementias. The view of Dr. Baker – and most other Alzheimer’s researchers – is to employ lifestyle changes to reduce risk as much as possible and not to stop when cognitive problems do present.

“We need to understand how lifestyle interventions might work in combination with pharmaceuticals,” she said. “If we can support the health of the body and the health of the mind, lifestyle interventions can be the fertilizer that would help drug therapy have its maximum effect.”

[email protected]

SAN DIEGO – To prevent dementia, follow Mom’s advice: Get up off the couch, go play with your friends, and eat your vegetables.

Michele G. Sullivan/MDedge News

After 15 years of disappointing drug trials, strong new evidence says the best way to attack Alzheimer’s disease is not to treat it once it develops, but to prevent it in the first place, Laura D. Baker, PhD, said at the Clinical Trials on Alzheimer’s Disease conference. Studies of exercise, cognitive and social stimulation, and diet show that each one can reduce the risk of dementia, and that a combination of all three may have even a more powerful and synergistic effect.

“We have become absolutely phobic of exercise,” said Dr. Baker of Wake Forest University, Winston-Salem, N.C. And it’s not just structured exercise we shirk. “We take the closest parking space, sit for hours on end, don’t even take the stairs. Yet we know from years of work that exercise has a powerful benefit on cardiovascular disease, lipid profiles, metabolic disease, stress, and mood. Now we are seeing that exercise also promotes brain health in normal aging and protects against cognitive decline and prevention.”
 

Get off the couch

The general benefits of exercise – chiefly aerobic exercise – are myriad, Dr. Baker said.

“Exercise increases effective neurorepair. It reduces oxidative stress. It improves insulin sensitivity and helps with maintaining normal weight. It reduces inflammation and increases normal clearance of amyloid-beta.”

A 2017 meta-analysis reviewed some of these findings. “The current review [of 16 studies] suggests that aerobic exercise may have positive effects on the right hippocampus and potentially beneficial effects on the overall and other parts of the hippocampus, the cingulate cortex, and the medial temporal areas. ... Moreover, aerobic exercise may increase functional connectivity or activation in the hippocampus, cingulate cortex, and parahippocampal gyrus regions,” wrote Mo-yi Li, PhD, of Fujian University of Traditional Chinese Medicine, Fuzhou, China, and colleagues.

Exercise increases brain-derived neurotrophic factor (BDNF), which in turn increases neuronal potentiation and synaptic plasticity. BDNF is also important in hippocampal neurogenesis; mice, after just one aerobic session, showed dramatic boosts in BDNF. A 2018 review elaborates on these findings.

Eat right

Diet mediates dementia risk through less direct, but very effective, pathways, Dr. Baker said. Diets rich in vegetables, berries, nuts, fish, lean proteins, and healthy fats improves virtually all metabolic measures. These, in turn, reduce the risk cerebrovascular disease – an important driver of vascular dementias and a contributor to Alzheimer’s disease risk as well.

The MIND diet study (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay), reported in 2015 was a very successful demonstration of this concept. A combination of the Mediterranean diet and the DASH diet (Dietary Approaches to Stop Hypertension), the MIND diet stresses frequent consumption of vegetables – especially leafy greens – as well as nuts, berries, whole grains, fish, poultry, and wine or grape juice. In the large, nearly 5-year study of 923 subjects aged 58-98 years, the MIND diet was associated with significant gains in cognition – equivalent to a 7-year reversal of age. After 4.5 years, those who strictly adhered to the diet had a 53% reduction in risk for Alzheimer’s disease, and those who adhered moderately had a 35% reduction. And in a more recent Australian longitudinal study, the MIND diet was associated with a 53% reduced risk of cognitive impairment over 12 years.

Ketogenic diets also may exert a benefit. Theoretically, a state of ketosis forces the brain to burn ketones as an alternative fuel to glucose, thus boosting brain function in glucose-starved brains. A small pilot study with exploratory cognitive endpoints determined that diet-compliant subjects with mild to moderate Alzheimer’s experienced a mean 5-point improvement in the Alzheimer’s Disease Assessment Score–Cognition. They reverted to baseline scores within a month of ending the study.

Recent initial work into the gut microbiome provides some additional speculative, but interesting, data. A dysregulated microbiome can shift microbial populations toward a more inflammatory profile. Some work suggests that inflammatory cytokines then travel to the brain and induce a hyperresponse of neuron-damaging immune cells. A comprehensive review article discusses the complicated mechanisms that may be in play.

Play with your friends

Cognitive stimulation and social interaction also appear to modify dementia risk, although the data are a little more limited. But personal interaction is a key element of Dr. Baker’s ongoing EXERT trial.

The ongoing phase 3 trial randomized 300 adults with amnestic mild cognitive impairment to moderate to high intensity aerobic exercise plus one-on-one support at local YMCA gyms or a low-intensity stretching, balance, and range of motion program. In additional to cognitive testing, the trial includes brain imaging, cerebrospinal fluid sampling for biomarkers of Alzheimer’s disease, and a sleep study.

A key component is personal interaction with a trainer. “They spend a lot of one-on-one time with each person,” Dr. Baker said. “For me, that’s the crucial ingredient – that personal touch. It’s what helps people move from Point A to Point B in their behaviors.”

Virtual cognitive stimulation is also a burgeoning area of dementia prevention research right now. Numerous studies are ongoing to test whether virtual reality or other computer-based games might keep the mind sharp or even improve cognition in people at risk.
 

The power of three

If one lifestyle change can reduce dementia risk, what happens when all three work together?

That’s the newest question, first successfully explored in the mid-2000s, with the FINGER study (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability). In FINGER, the triad of exercise, personal support at the gym, and a modified Mediterranean diet reduced Alzheimer’s disease risk and improved cognition relative to the control group.

FINGER showed that the intervention was feasible and that it was associated with cognitive preservation and reduced Alzheimer’s disease risk in a group of at-risk subjects. The active group also had a 25% greater improvement on a neuropsychological test battery relative to the control group. They also performed 150% better in processing speed, 83% better in executive function, and 40% better in short-term memory. They showed no increased risk of cognitive decline relative to the control group, which experienced a 30% increase in risk, according to lead investigator Miia Kivipelto, PhD, of the Karolinska Institute, Stockholm.

So successful was FINGER that it launched a global consortium of related studies called World Wide FINGERS. Active in six countries now, including the United States, the studies aim to discover whether such combinations of lifestyle interventions are workable across countries and cultures. World Wide FINGERS is largely supported by the Alzheimer’s Association.

Global enthusiasm for lifestyle interventions

In recognition of the importance of lifestyle changes for dementia prevention, the World Health Organization recently published “Risk reduction of cognitive decline and dementia.” The document reviews many studies and makes recommendations regarding not only exercise, diet, and cognitive stimulation, but also smoking and alcohol.

Research interest in these areas is surging, Dr. Baker said. “The [U.S.] National Institute on Aging now has 29 ongoing trials. There’s a strong commitment to investigations into how lifestyle interventions could protect brain health as we get older. Certainly, many fit and healthy people do develop Alzheimer’s. But for some, it could be medicine.”

But no matter how compliant people are, lifestyle changes will never completely rid the world of Alzheimer’s and other dementias. The view of Dr. Baker – and most other Alzheimer’s researchers – is to employ lifestyle changes to reduce risk as much as possible and not to stop when cognitive problems do present.

“We need to understand how lifestyle interventions might work in combination with pharmaceuticals,” she said. “If we can support the health of the body and the health of the mind, lifestyle interventions can be the fertilizer that would help drug therapy have its maximum effect.”

[email protected]

BALTIMORE – Candidates for epilepsy surgery who are employed are significantly more likely to decline surgery than are those who are unemployed, according to an analysis presented at the annual meeting of the American Epilepsy Society. “Future work should confirm this finding prospectively, determine if it holds in other patient populations, and explore the decision to proceed with or decline epilepsy surgery from a patient-centered perspective,” said Vishal Mandge, MD, MPH, a clinical neurophysiology fellow at Duke University in Durham, N.C., and colleagues. “Identifying the role that factors such as the fear of losing employment due to complications from surgery and inability to take medical leave for an extended period of time play in the patient’s decision to proceed with epilepsy surgery may identify needs and suggest strategies to reduce barriers to this underutilized treatment.”

Although epilepsy surgery is known to be safe and effective, many surgical candidates with drug-resistant epilepsy decline to undergo the procedure. Prior investigations of the barriers to epilepsy surgery have focused on access to epilepsy centers that offer epilepsy surgery and patients’ reluctance to undergo presurgical evaluation. Dr. Mandge and colleagues instead set out to evaluate the association between various demographic, disease-specific, and epilepsy-evaluation variables and patients’ decision to decline surgery after they have been identified as candidates.
 

A retrospective case-control study

The investigators conducted a retrospective case-control study of patients who were discussed at the epilepsy surgery conference of a tertiary care hospital serving an urban New York community between Jan. 1, 2009, and June 30, 2017. They identified patients who were considered candidates for resective epilepsy surgery. Dr. Mandge and colleagues used the chi-squared test for nominal variables and analysis of variance for scale variables to evaluate these variables’ associations with a patient’s decision to decline epilepsy surgery. They also performed multivariate binary logistic regression to identify variables that predict a patient’s decision to decline surgery.

Dr. Mandge and colleagues identified 159 patients who were discussed during the study period. Of this group, 87 patients were eligible for resective epilepsy surgery after a thorough evaluation. Thirty-four (40%) of the eligible patients declined to undergo surgery. Approximately 20% of eligible patients were employed, and 70% of patients had a high school diploma or higher education.

Univariate analysis indicated that employment (odds ratio, 4.2), temporal lesion on MRI (OR, 0.35), temporal EEG localization (OR, 0.21), and temporal seizure onset zone (OR, 0.19) were independently and significantly associated with a patient’s decision to decline surgery. Multivariate logistic regression analysis indicated that current employment (OR, 7.5), the number of current antiepileptic drugs (AEDs; OR, 3.5), and concordance between seizure semiology, seizure onset on EEG, and imaging (OR, 0.08) were significantly associated with a patient’s decision to decline surgery.
 

Fear of unemployment may explain results

“With each additional AED, the patients were 3.5 times more likely to decline surgery, even after adjusting for other variables,” said Alexis D. Boro, MD, a neurologist at Montefiore Medical Center in New York and one of the investigators. “My suspicion is that some of this reflects the burden of taking a lot of seizure medication. While the medications are much, much safer than seizures, and looking for and dealing with side effects is a lot of what we do, people often don’t feel great when they are taking multiple seizure medications. We counsel our patients that they should generally expect to stay on some seizure medications after surgery. The reason for surgery is to stop the seizures, not to stop the medications. We are often able to reduce medications after a period of time after surgery, and for many patients, this is one of the benefits.”

The association between employment and increased likelihood of declining surgery was unexpected and may not hold everywhere, said Dr. Boro. “We had expected the opposite result because we assumed that employed patients would be concerned that a seizure at work might result in loss of work. But it may be that many of our patients who are employed are concerned about losing their jobs if they miss work for a medical procedure. Some of our patients may be concerned about sharing medical information with their employers. For some of our patients, being employed may imply limited insurance coverage.”

The study was not supported by external funding, and the investigators did not report any disclosures.

[email protected]

SOURCE: Mandge VA et al. AES 2019, Abstract 1.362.

BALTIMORE – Candidates for epilepsy surgery who are employed are significantly more likely to decline surgery than are those who are unemployed, according to an analysis presented at the annual meeting of the American Epilepsy Society. “Future work should confirm this finding prospectively, determine if it holds in other patient populations, and explore the decision to proceed with or decline epilepsy surgery from a patient-centered perspective,” said Vishal Mandge, MD, MPH, a clinical neurophysiology fellow at Duke University in Durham, N.C., and colleagues. “Identifying the role that factors such as the fear of losing employment due to complications from surgery and inability to take medical leave for an extended period of time play in the patient’s decision to proceed with epilepsy surgery may identify needs and suggest strategies to reduce barriers to this underutilized treatment.”

Although epilepsy surgery is known to be safe and effective, many surgical candidates with drug-resistant epilepsy decline to undergo the procedure. Prior investigations of the barriers to epilepsy surgery have focused on access to epilepsy centers that offer epilepsy surgery and patients’ reluctance to undergo presurgical evaluation. Dr. Mandge and colleagues instead set out to evaluate the association between various demographic, disease-specific, and epilepsy-evaluation variables and patients’ decision to decline surgery after they have been identified as candidates.
 

A retrospective case-control study

The investigators conducted a retrospective case-control study of patients who were discussed at the epilepsy surgery conference of a tertiary care hospital serving an urban New York community between Jan. 1, 2009, and June 30, 2017. They identified patients who were considered candidates for resective epilepsy surgery. Dr. Mandge and colleagues used the chi-squared test for nominal variables and analysis of variance for scale variables to evaluate these variables’ associations with a patient’s decision to decline epilepsy surgery. They also performed multivariate binary logistic regression to identify variables that predict a patient’s decision to decline surgery.

Dr. Mandge and colleagues identified 159 patients who were discussed during the study period. Of this group, 87 patients were eligible for resective epilepsy surgery after a thorough evaluation. Thirty-four (40%) of the eligible patients declined to undergo surgery. Approximately 20% of eligible patients were employed, and 70% of patients had a high school diploma or higher education.

Univariate analysis indicated that employment (odds ratio, 4.2), temporal lesion on MRI (OR, 0.35), temporal EEG localization (OR, 0.21), and temporal seizure onset zone (OR, 0.19) were independently and significantly associated with a patient’s decision to decline surgery. Multivariate logistic regression analysis indicated that current employment (OR, 7.5), the number of current antiepileptic drugs (AEDs; OR, 3.5), and concordance between seizure semiology, seizure onset on EEG, and imaging (OR, 0.08) were significantly associated with a patient’s decision to decline surgery.
 

Fear of unemployment may explain results

“With each additional AED, the patients were 3.5 times more likely to decline surgery, even after adjusting for other variables,” said Alexis D. Boro, MD, a neurologist at Montefiore Medical Center in New York and one of the investigators. “My suspicion is that some of this reflects the burden of taking a lot of seizure medication. While the medications are much, much safer than seizures, and looking for and dealing with side effects is a lot of what we do, people often don’t feel great when they are taking multiple seizure medications. We counsel our patients that they should generally expect to stay on some seizure medications after surgery. The reason for surgery is to stop the seizures, not to stop the medications. We are often able to reduce medications after a period of time after surgery, and for many patients, this is one of the benefits.”

The association between employment and increased likelihood of declining surgery was unexpected and may not hold everywhere, said Dr. Boro. “We had expected the opposite result because we assumed that employed patients would be concerned that a seizure at work might result in loss of work. But it may be that many of our patients who are employed are concerned about losing their jobs if they miss work for a medical procedure. Some of our patients may be concerned about sharing medical information with their employers. For some of our patients, being employed may imply limited insurance coverage.”

The study was not supported by external funding, and the investigators did not report any disclosures.

[email protected]

SOURCE: Mandge VA et al. AES 2019, Abstract 1.362.

BALTIMORE – Candidates for epilepsy surgery who are employed are significantly more likely to decline surgery than are those who are unemployed, according to an analysis presented at the annual meeting of the American Epilepsy Society. “Future work should confirm this finding prospectively, determine if it holds in other patient populations, and explore the decision to proceed with or decline epilepsy surgery from a patient-centered perspective,” said Vishal Mandge, MD, MPH, a clinical neurophysiology fellow at Duke University in Durham, N.C., and colleagues. “Identifying the role that factors such as the fear of losing employment due to complications from surgery and inability to take medical leave for an extended period of time play in the patient’s decision to proceed with epilepsy surgery may identify needs and suggest strategies to reduce barriers to this underutilized treatment.”

Although epilepsy surgery is known to be safe and effective, many surgical candidates with drug-resistant epilepsy decline to undergo the procedure. Prior investigations of the barriers to epilepsy surgery have focused on access to epilepsy centers that offer epilepsy surgery and patients’ reluctance to undergo presurgical evaluation. Dr. Mandge and colleagues instead set out to evaluate the association between various demographic, disease-specific, and epilepsy-evaluation variables and patients’ decision to decline surgery after they have been identified as candidates.
 

A retrospective case-control study

The investigators conducted a retrospective case-control study of patients who were discussed at the epilepsy surgery conference of a tertiary care hospital serving an urban New York community between Jan. 1, 2009, and June 30, 2017. They identified patients who were considered candidates for resective epilepsy surgery. Dr. Mandge and colleagues used the chi-squared test for nominal variables and analysis of variance for scale variables to evaluate these variables’ associations with a patient’s decision to decline epilepsy surgery. They also performed multivariate binary logistic regression to identify variables that predict a patient’s decision to decline surgery.

Dr. Mandge and colleagues identified 159 patients who were discussed during the study period. Of this group, 87 patients were eligible for resective epilepsy surgery after a thorough evaluation. Thirty-four (40%) of the eligible patients declined to undergo surgery. Approximately 20% of eligible patients were employed, and 70% of patients had a high school diploma or higher education.

Univariate analysis indicated that employment (odds ratio, 4.2), temporal lesion on MRI (OR, 0.35), temporal EEG localization (OR, 0.21), and temporal seizure onset zone (OR, 0.19) were independently and significantly associated with a patient’s decision to decline surgery. Multivariate logistic regression analysis indicated that current employment (OR, 7.5), the number of current antiepileptic drugs (AEDs; OR, 3.5), and concordance between seizure semiology, seizure onset on EEG, and imaging (OR, 0.08) were significantly associated with a patient’s decision to decline surgery.
 

Fear of unemployment may explain results

“With each additional AED, the patients were 3.5 times more likely to decline surgery, even after adjusting for other variables,” said Alexis D. Boro, MD, a neurologist at Montefiore Medical Center in New York and one of the investigators. “My suspicion is that some of this reflects the burden of taking a lot of seizure medication. While the medications are much, much safer than seizures, and looking for and dealing with side effects is a lot of what we do, people often don’t feel great when they are taking multiple seizure medications. We counsel our patients that they should generally expect to stay on some seizure medications after surgery. The reason for surgery is to stop the seizures, not to stop the medications. We are often able to reduce medications after a period of time after surgery, and for many patients, this is one of the benefits.”

The association between employment and increased likelihood of declining surgery was unexpected and may not hold everywhere, said Dr. Boro. “We had expected the opposite result because we assumed that employed patients would be concerned that a seizure at work might result in loss of work. But it may be that many of our patients who are employed are concerned about losing their jobs if they miss work for a medical procedure. Some of our patients may be concerned about sharing medical information with their employers. For some of our patients, being employed may imply limited insurance coverage.”

The study was not supported by external funding, and the investigators did not report any disclosures.

[email protected]

SOURCE: Mandge VA et al. AES 2019, Abstract 1.362.

SAN DIEGO – Pimavanserin, a second-generation antipsychotic approved for hallucinations and delusions in patients with Parkinson’s disease, may also be helpful for psychotic symptoms in other dementia patients, Erin P. Foff, MD, said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

In fact, the phase 3 HARMONY trial was stopped early, after an interim efficacy analysis determined that treatment with pimavanserin (Nuplazid) had achieved its primary endpoint – a statistically significant threefold reduction in the risk of relapse (P less than .0033).

Importantly, pimavanserin didn’t significantly affect cognition nor, at least in this controlled setting, did it appear to increase falls or other adverse events often seen with antipsychotic use in elderly patients, said Dr. Foff, clinical lead for the dementia-related psychosis program at Acadia Pharmaceuticals, which makes the drug and sponsored the study.

Based on the positive results, Acadia intends to submit a supplemental new drug application for this indication, according to an investor presentation posted on the company website.

“There is a critical need for an intervention [for psychosis symptoms] in this population,” Dr. Foff said. “We saw a robust response that was well tolerated and well maintained with no negative impact on cognitive scores.”

The second-generation antipsychotic was approved in 2016 for treating hallucinations and delusions in patients with Parkinson’s disease.

The drug is a selective antagonist of 5-HT₂ receptors, with low affinity for dopamine receptors. This slightly differentiates it from other second-generation antipsychotics that affect dopamine receptors as well as 5-HT₂ receptors.

HARMONY was not a typical placebo-controlled, randomized efficacy trial. Rather, it employed a two-phase design: an open-label treatment response period followed by a placebo-controlled randomization limited to open-label responders. Overall, HARMONY involved 392 patients with mild to severe dementia of numerous etiologies, including Alzheimer’s disease (66.8%), Parkinson’s disease dementia (14.3%), frontotemporal dementia (1.8%), vascular dementia (9.7%), and dementia with Lewy bodies (7.4%). All patients entered a 12-week, open-label period during which they received pimavanserin 34 mg daily. The primary endpoint was a combination of least a 30% reduction on the total Scale for the Assessment of Positive Symptom–Hallucinations and Delusions (SAPS-HD) scale plus a score of 1-2 on the Clinical Global Impressions–Improvement (CGI-I) scale, meaning better or very much better.

At 12 weeks, all responders were then randomized to placebo or continued therapy for 26 weeks. The primary endpoint was relapse, defined as at least a 30% worsening of the SAPS-HD relative to open-label baseline, plus a CGI-I score of 6-7 (worse or very much worse).

Patients were aged a mean of 74 years. Most (about 90%) were living at home. Visual hallucinations occurred in 80% and delusions in 83%. At baseline, the mean SAPS-HD score was 24.4, and the mean CGI-Severity score was 4.7. The mean Mini-Mental State Exam (MMSE) score was 16.7.

In the open-label period, pimavanserin reduced the SAPS-HD score at 12 weeks by a mean of 75%. Symptoms began to decline in the first week of treatment, with continuing improvement throughout the treatment period. By week 4, 30% had hit the response target. This number increased steadily, with 51% responding by week 4, 75% by week 8, and 88% by week 12.

By probable diagnosis, response rates were 59.8% in Alzheimer’s patients, 45.5% for those with Lewy body dementia, 71.2% among patients with Parkinson’s disease, 71% in patients with vascular dementia, and 50% in patients with frontotemporal dementia. In the final analysis, 80% of patients overall were considered responders.

The randomized potion began immediately thereafter with no washout period. About 62% (194) of the entire cohort – all responders – entered into the placebo-controlled phase. The remaining patients were either not responders (20%), dropped out because of an adverse event (7.7%), or left the study for unspecified reasons (10%). There was one death, which was not related to the study medication. A total of 41 patients were still being treated when the study was discontinued, and they were excluded from the final analysis.

When the randomized study ended, relapses had occurred in 28.3% of those taking placebo and in 12.6% of those taking pimavanserin – a statistically significant difference (hazard ratio, 0.353). This translated to a 180% reduction in relapse.

The rate of adverse events was similar in both active and placebo groups (41% vs. 36.6%). Serious adverse events occurred in 4.8% and 3.6%, respectively. The most commonly reported adverse events were headache (9.5% vs. 4.5%) and urinary tract infection (6.7% vs. 3.6%). Asthenia occurred in 2.9% of treated patients and 0.9% of placebo patients, but no falls were reported. Anxiety and dizziness were also reported in three patients taking the study medication.

Three patients (2.9%) experienced a prolonged QT phase on ECG, with a mean delay of 5.4 milliseconds from baseline. “Pimavanserin is known to have this effect of QT prolongation,” Dr. Foff said. “This 5.4-ms change is exactly in line with what we already know about pimavanserin and is not clinically significant. We saw no effect on motor function, consistent with the mechanism of action, and very low levels of agitation or aggression.”

Pimavanserin didn’t significantly change cognition from baseline in the open-label period, and in the randomized period, MMSE never differed significantly between groups.

The company also conducted an exploratory subgroup analysis that looked at placebo versus pimavanserin relapse by probable clinical diagnosis. Among the types of dementia, relapse rates for placebo versus pimavanserin were 23% versus 13% among Alzheimer’s patients, 67% versus 0% in Lewy body dementia patients, 50% versus 7% in patients with Parkinson’s, and 17% each among vascular dementia patients. Only one patient in the randomized period had frontotemporal dementia, and that patient relapsed on treatment.

Whether pimavanserin is effective specifically for psychosis in Alzheimer’s disease patients, however, remains in question. In 2018, Acadia published a negative phase 2 trial in a targeted group of 181 Alzheimer’s patients. The primary outcome in each study was mean change on the Neuropsychiatric Inventory–Nursing Home Version psychosis score (NPI-NH-PS). Clive Ballard, MD, of the University of Exeter (England), was the primary investigator.

After 6 weeks, those taking pimavanserin had a 3.76-point change in the NPI-NH-PS, compared with a 1.93-point change in the placebo group. The mean 1.84-point difference was not statistically significant.

This Alzheimer’s-only cohort group also experienced more adverse events than the HARMONY mixed-diagnosis cohort did, although the differences between pimavanserin and placebo groups were not significant. Adverse events included falls (23% of each group) and agitation (21% with pimavanserin vs. 14% with placebo). Cognition was unaffected.

Later that year, Acadia published a subgroup analysis of the same cohort parsing response by symptom severity, again with Dr. Ballard as the lead investigator.

The analysis focused on 57 patients with a baseline NPI-NH-PS of at least 12, indicating severe symptoms of psychosis.

Treatment effects were more pronounced in this group, significantly favoring pimavanserin. On the NPI-NH-PS, 88.9% of the pimavanserin group and 43.3% of the placebo group had at least a 30% improvement; 77.8% and 43.3% experienced at least a 50% improvement. The rate of serious adverse events was similar (18% with pimavanserin and 17% with placebo) and cognition was unaffected. Falls occurred in 14% of the treated group and 20% of the placebo group.

“These findings coupled with the results from other studies of pimavanserin suggest a potential role for pimavanserin in treating psychosis in patients across a range of neuropsychiatric conditions,” Dr. Ballard wrote.

[email protected]

SOURCE: Foff EP et al. CTAD 2019, Late-breaker 1

SAN DIEGO – Pimavanserin, a second-generation antipsychotic approved for hallucinations and delusions in patients with Parkinson’s disease, may also be helpful for psychotic symptoms in other dementia patients, Erin P. Foff, MD, said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

In fact, the phase 3 HARMONY trial was stopped early, after an interim efficacy analysis determined that treatment with pimavanserin (Nuplazid) had achieved its primary endpoint – a statistically significant threefold reduction in the risk of relapse (P less than .0033).

Importantly, pimavanserin didn’t significantly affect cognition nor, at least in this controlled setting, did it appear to increase falls or other adverse events often seen with antipsychotic use in elderly patients, said Dr. Foff, clinical lead for the dementia-related psychosis program at Acadia Pharmaceuticals, which makes the drug and sponsored the study.

Based on the positive results, Acadia intends to submit a supplemental new drug application for this indication, according to an investor presentation posted on the company website.

“There is a critical need for an intervention [for psychosis symptoms] in this population,” Dr. Foff said. “We saw a robust response that was well tolerated and well maintained with no negative impact on cognitive scores.”

The second-generation antipsychotic was approved in 2016 for treating hallucinations and delusions in patients with Parkinson’s disease.

The drug is a selective antagonist of 5-HT₂ receptors, with low affinity for dopamine receptors. This slightly differentiates it from other second-generation antipsychotics that affect dopamine receptors as well as 5-HT₂ receptors.

HARMONY was not a typical placebo-controlled, randomized efficacy trial. Rather, it employed a two-phase design: an open-label treatment response period followed by a placebo-controlled randomization limited to open-label responders. Overall, HARMONY involved 392 patients with mild to severe dementia of numerous etiologies, including Alzheimer’s disease (66.8%), Parkinson’s disease dementia (14.3%), frontotemporal dementia (1.8%), vascular dementia (9.7%), and dementia with Lewy bodies (7.4%). All patients entered a 12-week, open-label period during which they received pimavanserin 34 mg daily. The primary endpoint was a combination of least a 30% reduction on the total Scale for the Assessment of Positive Symptom–Hallucinations and Delusions (SAPS-HD) scale plus a score of 1-2 on the Clinical Global Impressions–Improvement (CGI-I) scale, meaning better or very much better.

At 12 weeks, all responders were then randomized to placebo or continued therapy for 26 weeks. The primary endpoint was relapse, defined as at least a 30% worsening of the SAPS-HD relative to open-label baseline, plus a CGI-I score of 6-7 (worse or very much worse).

Patients were aged a mean of 74 years. Most (about 90%) were living at home. Visual hallucinations occurred in 80% and delusions in 83%. At baseline, the mean SAPS-HD score was 24.4, and the mean CGI-Severity score was 4.7. The mean Mini-Mental State Exam (MMSE) score was 16.7.

In the open-label period, pimavanserin reduced the SAPS-HD score at 12 weeks by a mean of 75%. Symptoms began to decline in the first week of treatment, with continuing improvement throughout the treatment period. By week 4, 30% had hit the response target. This number increased steadily, with 51% responding by week 4, 75% by week 8, and 88% by week 12.

By probable diagnosis, response rates were 59.8% in Alzheimer’s patients, 45.5% for those with Lewy body dementia, 71.2% among patients with Parkinson’s disease, 71% in patients with vascular dementia, and 50% in patients with frontotemporal dementia. In the final analysis, 80% of patients overall were considered responders.

The randomized potion began immediately thereafter with no washout period. About 62% (194) of the entire cohort – all responders – entered into the placebo-controlled phase. The remaining patients were either not responders (20%), dropped out because of an adverse event (7.7%), or left the study for unspecified reasons (10%). There was one death, which was not related to the study medication. A total of 41 patients were still being treated when the study was discontinued, and they were excluded from the final analysis.

When the randomized study ended, relapses had occurred in 28.3% of those taking placebo and in 12.6% of those taking pimavanserin – a statistically significant difference (hazard ratio, 0.353). This translated to a 180% reduction in relapse.

The rate of adverse events was similar in both active and placebo groups (41% vs. 36.6%). Serious adverse events occurred in 4.8% and 3.6%, respectively. The most commonly reported adverse events were headache (9.5% vs. 4.5%) and urinary tract infection (6.7% vs. 3.6%). Asthenia occurred in 2.9% of treated patients and 0.9% of placebo patients, but no falls were reported. Anxiety and dizziness were also reported in three patients taking the study medication.

Three patients (2.9%) experienced a prolonged QT phase on ECG, with a mean delay of 5.4 milliseconds from baseline. “Pimavanserin is known to have this effect of QT prolongation,” Dr. Foff said. “This 5.4-ms change is exactly in line with what we already know about pimavanserin and is not clinically significant. We saw no effect on motor function, consistent with the mechanism of action, and very low levels of agitation or aggression.”

Pimavanserin didn’t significantly change cognition from baseline in the open-label period, and in the randomized period, MMSE never differed significantly between groups.

The company also conducted an exploratory subgroup analysis that looked at placebo versus pimavanserin relapse by probable clinical diagnosis. Among the types of dementia, relapse rates for placebo versus pimavanserin were 23% versus 13% among Alzheimer’s patients, 67% versus 0% in Lewy body dementia patients, 50% versus 7% in patients with Parkinson’s, and 17% each among vascular dementia patients. Only one patient in the randomized period had frontotemporal dementia, and that patient relapsed on treatment.

Whether pimavanserin is effective specifically for psychosis in Alzheimer’s disease patients, however, remains in question. In 2018, Acadia published a negative phase 2 trial in a targeted group of 181 Alzheimer’s patients. The primary outcome in each study was mean change on the Neuropsychiatric Inventory–Nursing Home Version psychosis score (NPI-NH-PS). Clive Ballard, MD, of the University of Exeter (England), was the primary investigator.

After 6 weeks, those taking pimavanserin had a 3.76-point change in the NPI-NH-PS, compared with a 1.93-point change in the placebo group. The mean 1.84-point difference was not statistically significant.

This Alzheimer’s-only cohort group also experienced more adverse events than the HARMONY mixed-diagnosis cohort did, although the differences between pimavanserin and placebo groups were not significant. Adverse events included falls (23% of each group) and agitation (21% with pimavanserin vs. 14% with placebo). Cognition was unaffected.

Later that year, Acadia published a subgroup analysis of the same cohort parsing response by symptom severity, again with Dr. Ballard as the lead investigator.

The analysis focused on 57 patients with a baseline NPI-NH-PS of at least 12, indicating severe symptoms of psychosis.

Treatment effects were more pronounced in this group, significantly favoring pimavanserin. On the NPI-NH-PS, 88.9% of the pimavanserin group and 43.3% of the placebo group had at least a 30% improvement; 77.8% and 43.3% experienced at least a 50% improvement. The rate of serious adverse events was similar (18% with pimavanserin and 17% with placebo) and cognition was unaffected. Falls occurred in 14% of the treated group and 20% of the placebo group.

“These findings coupled with the results from other studies of pimavanserin suggest a potential role for pimavanserin in treating psychosis in patients across a range of neuropsychiatric conditions,” Dr. Ballard wrote.

[email protected]

SOURCE: Foff EP et al. CTAD 2019, Late-breaker 1

SAN DIEGO – Pimavanserin, a second-generation antipsychotic approved for hallucinations and delusions in patients with Parkinson’s disease, may also be helpful for psychotic symptoms in other dementia patients, Erin P. Foff, MD, said at the Clinical Trials on Alzheimer’s Disease conference.

Michele G. Sullivan/MDedge News

In fact, the phase 3 HARMONY trial was stopped early, after an interim efficacy analysis determined that treatment with pimavanserin (Nuplazid) had achieved its primary endpoint – a statistically significant threefold reduction in the risk of relapse (P less than .0033).

Importantly, pimavanserin didn’t significantly affect cognition nor, at least in this controlled setting, did it appear to increase falls or other adverse events often seen with antipsychotic use in elderly patients, said Dr. Foff, clinical lead for the dementia-related psychosis program at Acadia Pharmaceuticals, which makes the drug and sponsored the study.

Based on the positive results, Acadia intends to submit a supplemental new drug application for this indication, according to an investor presentation posted on the company website.

“There is a critical need for an intervention [for psychosis symptoms] in this population,” Dr. Foff said. “We saw a robust response that was well tolerated and well maintained with no negative impact on cognitive scores.”

The second-generation antipsychotic was approved in 2016 for treating hallucinations and delusions in patients with Parkinson’s disease.

The drug is a selective antagonist of 5-HT₂ receptors, with low affinity for dopamine receptors. This slightly differentiates it from other second-generation antipsychotics that affect dopamine receptors as well as 5-HT₂ receptors.

HARMONY was not a typical placebo-controlled, randomized efficacy trial. Rather, it employed a two-phase design: an open-label treatment response period followed by a placebo-controlled randomization limited to open-label responders. Overall, HARMONY involved 392 patients with mild to severe dementia of numerous etiologies, including Alzheimer’s disease (66.8%), Parkinson’s disease dementia (14.3%), frontotemporal dementia (1.8%), vascular dementia (9.7%), and dementia with Lewy bodies (7.4%). All patients entered a 12-week, open-label period during which they received pimavanserin 34 mg daily. The primary endpoint was a combination of least a 30% reduction on the total Scale for the Assessment of Positive Symptom–Hallucinations and Delusions (SAPS-HD) scale plus a score of 1-2 on the Clinical Global Impressions–Improvement (CGI-I) scale, meaning better or very much better.

At 12 weeks, all responders were then randomized to placebo or continued therapy for 26 weeks. The primary endpoint was relapse, defined as at least a 30% worsening of the SAPS-HD relative to open-label baseline, plus a CGI-I score of 6-7 (worse or very much worse).

Patients were aged a mean of 74 years. Most (about 90%) were living at home. Visual hallucinations occurred in 80% and delusions in 83%. At baseline, the mean SAPS-HD score was 24.4, and the mean CGI-Severity score was 4.7. The mean Mini-Mental State Exam (MMSE) score was 16.7.

In the open-label period, pimavanserin reduced the SAPS-HD score at 12 weeks by a mean of 75%. Symptoms began to decline in the first week of treatment, with continuing improvement throughout the treatment period. By week 4, 30% had hit the response target. This number increased steadily, with 51% responding by week 4, 75% by week 8, and 88% by week 12.

By probable diagnosis, response rates were 59.8% in Alzheimer’s patients, 45.5% for those with Lewy body dementia, 71.2% among patients with Parkinson’s disease, 71% in patients with vascular dementia, and 50% in patients with frontotemporal dementia. In the final analysis, 80% of patients overall were considered responders.

The randomized potion began immediately thereafter with no washout period. About 62% (194) of the entire cohort – all responders – entered into the placebo-controlled phase. The remaining patients were either not responders (20%), dropped out because of an adverse event (7.7%), or left the study for unspecified reasons (10%). There was one death, which was not related to the study medication. A total of 41 patients were still being treated when the study was discontinued, and they were excluded from the final analysis.

When the randomized study ended, relapses had occurred in 28.3% of those taking placebo and in 12.6% of those taking pimavanserin – a statistically significant difference (hazard ratio, 0.353). This translated to a 180% reduction in relapse.

The rate of adverse events was similar in both active and placebo groups (41% vs. 36.6%). Serious adverse events occurred in 4.8% and 3.6%, respectively. The most commonly reported adverse events were headache (9.5% vs. 4.5%) and urinary tract infection (6.7% vs. 3.6%). Asthenia occurred in 2.9% of treated patients and 0.9% of placebo patients, but no falls were reported. Anxiety and dizziness were also reported in three patients taking the study medication.

Three patients (2.9%) experienced a prolonged QT phase on ECG, with a mean delay of 5.4 milliseconds from baseline. “Pimavanserin is known to have this effect of QT prolongation,” Dr. Foff said. “This 5.4-ms change is exactly in line with what we already know about pimavanserin and is not clinically significant. We saw no effect on motor function, consistent with the mechanism of action, and very low levels of agitation or aggression.”

Pimavanserin didn’t significantly change cognition from baseline in the open-label period, and in the randomized period, MMSE never differed significantly between groups.

The company also conducted an exploratory subgroup analysis that looked at placebo versus pimavanserin relapse by probable clinical diagnosis. Among the types of dementia, relapse rates for placebo versus pimavanserin were 23% versus 13% among Alzheimer’s patients, 67% versus 0% in Lewy body dementia patients, 50% versus 7% in patients with Parkinson’s, and 17% each among vascular dementia patients. Only one patient in the randomized period had frontotemporal dementia, and that patient relapsed on treatment.

Whether pimavanserin is effective specifically for psychosis in Alzheimer’s disease patients, however, remains in question. In 2018, Acadia published a negative phase 2 trial in a targeted group of 181 Alzheimer’s patients. The primary outcome in each study was mean change on the Neuropsychiatric Inventory–Nursing Home Version psychosis score (NPI-NH-PS). Clive Ballard, MD, of the University of Exeter (England), was the primary investigator.

After 6 weeks, those taking pimavanserin had a 3.76-point change in the NPI-NH-PS, compared with a 1.93-point change in the placebo group. The mean 1.84-point difference was not statistically significant.

This Alzheimer’s-only cohort group also experienced more adverse events than the HARMONY mixed-diagnosis cohort did, although the differences between pimavanserin and placebo groups were not significant. Adverse events included falls (23% of each group) and agitation (21% with pimavanserin vs. 14% with placebo). Cognition was unaffected.

Later that year, Acadia published a subgroup analysis of the same cohort parsing response by symptom severity, again with Dr. Ballard as the lead investigator.

The analysis focused on 57 patients with a baseline NPI-NH-PS of at least 12, indicating severe symptoms of psychosis.

Treatment effects were more pronounced in this group, significantly favoring pimavanserin. On the NPI-NH-PS, 88.9% of the pimavanserin group and 43.3% of the placebo group had at least a 30% improvement; 77.8% and 43.3% experienced at least a 50% improvement. The rate of serious adverse events was similar (18% with pimavanserin and 17% with placebo) and cognition was unaffected. Falls occurred in 14% of the treated group and 20% of the placebo group.

“These findings coupled with the results from other studies of pimavanserin suggest a potential role for pimavanserin in treating psychosis in patients across a range of neuropsychiatric conditions,” Dr. Ballard wrote.

[email protected]

SOURCE: Foff EP et al. CTAD 2019, Late-breaker 1

BALTIMORE – Patients hospitalized for epilepsy may have higher odds of death if they have a secondary diagnosis of arrhythmia, whereas the presence of apnea alone may not significantly increase mortality, according to an analysis of data from the Nationwide Inpatient Sample presented at the annual meeting of the American Epilepsy Society.

Jake Remaly/MDedge News

“If you have someone with arrhythmia and epilepsy, you have to be more concerned about possible SUDEP [sudden unexpected death in epilepsy],” relative to someone with apnea and epilepsy, said senior study author Sanjay P. Singh, MD, professor of neurology at Creighton University, Omaha, Neb.

Research indicates that apnea and cardiac arrhythmias may contribute to SUDEP, and the incidence of SUDEP is higher in patients with intractable epilepsy.

To identify the prevalence of apnea, arrhythmia, and both conditions in epilepsy hospitalizations, as well as the prevalence of intractable epilepsy and mortality, Dr. Singh and colleagues performed a retrospective, cross-sectional analysis of pediatric and adult epilepsy hospitalizations between 2003 and 2014 in the Nationwide Inpatient Sample. They determined apnea and arrhythmia diagnoses using ICD-9-CM codes.

Among more than 2.6 million epilepsy hospitalizations, the prevalence of apnea was 2.75%, the prevalence of arrhythmia was 8.91%, and the prevalence of both was 0.49%. The proportion of patients with intractable epilepsy was 7.7%. Among the more than 207,000 hospitalizations with intractable epilepsy, the prevalence of apnea was 3.62%, the prevalence of arrhythmia was 3.34%, and the prevalence of both was 0.36%. The prevalence trend of apnea, arrhythmia, and both together increased between 2003 and 2014.

“In univariate analysis, prevalence of mortality was highest among patients with arrhythmia,” the researchers reported, at – 3.1% in patients with arrhythmia versus 0.48% in patients with apnea, 2.91% in patients with both, and 0.46% in patients without apnea or arrhythmia.

In a multivariable regression analysis, significant and independent predictors of death included intractable epilepsy (odds ratio, 1.17), apnea (OR, 0.84), arrhythmia (OR, 3.29), and the presence of both apnea and arrhythmia (OR, 3.24). When hospitalization was complicated by intractable epilepsy, the odds of death rose with the presence of apnea (OR, 2.07), arrhythmia (OR, 8.39), and with both apnea and arrhythmia (OR, 11.64).

The results highlight the importance of effective epilepsy management, said first author Urvish K. Patel, MBBS, also with Creighton University. “If we can stop [conversion to intractable epilepsy], then this odds ratio can go down.”

Attention to arrhythmias, as well as the combination of arrhythmias and apnea, may “be important in identifying patients at risk for SUDEP,” the authors concluded.

The researchers had no disclosures and reported receiving no outside funding for their work.

[email protected]

SOURCE: Patel UK et al. AES 2019, Abstract 2.140.

BALTIMORE – Patients hospitalized for epilepsy may have higher odds of death if they have a secondary diagnosis of arrhythmia, whereas the presence of apnea alone may not significantly increase mortality, according to an analysis of data from the Nationwide Inpatient Sample presented at the annual meeting of the American Epilepsy Society.

Jake Remaly/MDedge News

“If you have someone with arrhythmia and epilepsy, you have to be more concerned about possible SUDEP [sudden unexpected death in epilepsy],” relative to someone with apnea and epilepsy, said senior study author Sanjay P. Singh, MD, professor of neurology at Creighton University, Omaha, Neb.

Research indicates that apnea and cardiac arrhythmias may contribute to SUDEP, and the incidence of SUDEP is higher in patients with intractable epilepsy.

To identify the prevalence of apnea, arrhythmia, and both conditions in epilepsy hospitalizations, as well as the prevalence of intractable epilepsy and mortality, Dr. Singh and colleagues performed a retrospective, cross-sectional analysis of pediatric and adult epilepsy hospitalizations between 2003 and 2014 in the Nationwide Inpatient Sample. They determined apnea and arrhythmia diagnoses using ICD-9-CM codes.

Among more than 2.6 million epilepsy hospitalizations, the prevalence of apnea was 2.75%, the prevalence of arrhythmia was 8.91%, and the prevalence of both was 0.49%. The proportion of patients with intractable epilepsy was 7.7%. Among the more than 207,000 hospitalizations with intractable epilepsy, the prevalence of apnea was 3.62%, the prevalence of arrhythmia was 3.34%, and the prevalence of both was 0.36%. The prevalence trend of apnea, arrhythmia, and both together increased between 2003 and 2014.

“In univariate analysis, prevalence of mortality was highest among patients with arrhythmia,” the researchers reported, at – 3.1% in patients with arrhythmia versus 0.48% in patients with apnea, 2.91% in patients with both, and 0.46% in patients without apnea or arrhythmia.

In a multivariable regression analysis, significant and independent predictors of death included intractable epilepsy (odds ratio, 1.17), apnea (OR, 0.84), arrhythmia (OR, 3.29), and the presence of both apnea and arrhythmia (OR, 3.24). When hospitalization was complicated by intractable epilepsy, the odds of death rose with the presence of apnea (OR, 2.07), arrhythmia (OR, 8.39), and with both apnea and arrhythmia (OR, 11.64).

The results highlight the importance of effective epilepsy management, said first author Urvish K. Patel, MBBS, also with Creighton University. “If we can stop [conversion to intractable epilepsy], then this odds ratio can go down.”

Attention to arrhythmias, as well as the combination of arrhythmias and apnea, may “be important in identifying patients at risk for SUDEP,” the authors concluded.

The researchers had no disclosures and reported receiving no outside funding for their work.

[email protected]

SOURCE: Patel UK et al. AES 2019, Abstract 2.140.

BALTIMORE – Patients hospitalized for epilepsy may have higher odds of death if they have a secondary diagnosis of arrhythmia, whereas the presence of apnea alone may not significantly increase mortality, according to an analysis of data from the Nationwide Inpatient Sample presented at the annual meeting of the American Epilepsy Society.

Jake Remaly/MDedge News

“If you have someone with arrhythmia and epilepsy, you have to be more concerned about possible SUDEP [sudden unexpected death in epilepsy],” relative to someone with apnea and epilepsy, said senior study author Sanjay P. Singh, MD, professor of neurology at Creighton University, Omaha, Neb.

Research indicates that apnea and cardiac arrhythmias may contribute to SUDEP, and the incidence of SUDEP is higher in patients with intractable epilepsy.

To identify the prevalence of apnea, arrhythmia, and both conditions in epilepsy hospitalizations, as well as the prevalence of intractable epilepsy and mortality, Dr. Singh and colleagues performed a retrospective, cross-sectional analysis of pediatric and adult epilepsy hospitalizations between 2003 and 2014 in the Nationwide Inpatient Sample. They determined apnea and arrhythmia diagnoses using ICD-9-CM codes.

Among more than 2.6 million epilepsy hospitalizations, the prevalence of apnea was 2.75%, the prevalence of arrhythmia was 8.91%, and the prevalence of both was 0.49%. The proportion of patients with intractable epilepsy was 7.7%. Among the more than 207,000 hospitalizations with intractable epilepsy, the prevalence of apnea was 3.62%, the prevalence of arrhythmia was 3.34%, and the prevalence of both was 0.36%. The prevalence trend of apnea, arrhythmia, and both together increased between 2003 and 2014.

“In univariate analysis, prevalence of mortality was highest among patients with arrhythmia,” the researchers reported, at – 3.1% in patients with arrhythmia versus 0.48% in patients with apnea, 2.91% in patients with both, and 0.46% in patients without apnea or arrhythmia.

In a multivariable regression analysis, significant and independent predictors of death included intractable epilepsy (odds ratio, 1.17), apnea (OR, 0.84), arrhythmia (OR, 3.29), and the presence of both apnea and arrhythmia (OR, 3.24). When hospitalization was complicated by intractable epilepsy, the odds of death rose with the presence of apnea (OR, 2.07), arrhythmia (OR, 8.39), and with both apnea and arrhythmia (OR, 11.64).

The results highlight the importance of effective epilepsy management, said first author Urvish K. Patel, MBBS, also with Creighton University. “If we can stop [conversion to intractable epilepsy], then this odds ratio can go down.”

Attention to arrhythmias, as well as the combination of arrhythmias and apnea, may “be important in identifying patients at risk for SUDEP,” the authors concluded.

The researchers had no disclosures and reported receiving no outside funding for their work.

[email protected]

SOURCE: Patel UK et al. AES 2019, Abstract 2.140.

BALTIMORE – Sodium channel blocker antiepileptic drugs increase the risk of infantile spasms sevenfold in children with Down syndrome, tuberous sclerosis complex, hypoxic-ischemic encephalopathy, and other nonsyndromic epilepsy conditions with infantile spasms, according to a case-control review from the University of California, Los Angeles. “This is scary and warrants caution,” said senior investigator and pediatric neurologist Shaun Hussain, MD, a pediatric neurologist at Mattel Children’s Hospital at UCLA. Because of the findings, “we are avoiding the use of voltage-gated sodium channel blockade in any child at risk for infantile spasms. More broadly, we are avoiding [them] in any infant if there is a good alternative medication, of which there are many in most cases.”

There have been a few previous case reports linking voltage-gated sodium channel blockers (SCBs) – which include oxcarbazepine, carbamazepine, lacosamide, and phenytoin – to infantile spasms, but they are still commonly used for infant seizures. There was some disagreement at UCLA whether there really was a link, so Dr. Hussain and his team took a look at the university’s experience. They matched 50 children with nonsyndromic epilepsy who subsequently developed video-EEG confirmed infantile spasms (cases) to 50 children who also had nonsyndromic epilepsy but did not develop spasms, based on follow-up duration and age and date of epilepsy onset.

The team then looked to see what drugs they had been on; it turned out that cases and controls were about equally as likely to have been treated with any specific antiepileptic, including SCBs. Infantile spasms were substantially more likely with SCB exposure in children with spasm risk factors, which also include focal cortical dysplasia, Aicardi syndrome, and other problems (HR 7.0; 95%; CI 2.5-19.8; P less than .001). Spasms were also more likely among even low-risk children treated with SCBs, although the trend was not statistically significant.

In the end, “we wonder how many cases of infantile spasms could [have been] prevented entirely if we had avoided sodium channel blockade,” Dr. Hussain said at the annual meeting of the American Epilepsy Society.

With so many other seizure options available – levetiracetam, topiramate, and phenobarbital, to name just a few – maybe it would be best “to stay away from” SCBs entirely in “infants with any form of epilepsy,” said lead investigator Jaeden Heesch, an undergraduate researcher who worked with Dr. Hussain.

M. Alexander Otto/MDedge News

[email protected]

SOURCE: Heesch J et al. AES 2019. Abstract 2.234.

BALTIMORE – Sodium channel blocker antiepileptic drugs increase the risk of infantile spasms sevenfold in children with Down syndrome, tuberous sclerosis complex, hypoxic-ischemic encephalopathy, and other nonsyndromic epilepsy conditions with infantile spasms, according to a case-control review from the University of California, Los Angeles. “This is scary and warrants caution,” said senior investigator and pediatric neurologist Shaun Hussain, MD, a pediatric neurologist at Mattel Children’s Hospital at UCLA. Because of the findings, “we are avoiding the use of voltage-gated sodium channel blockade in any child at risk for infantile spasms. More broadly, we are avoiding [them] in any infant if there is a good alternative medication, of which there are many in most cases.”

There have been a few previous case reports linking voltage-gated sodium channel blockers (SCBs) – which include oxcarbazepine, carbamazepine, lacosamide, and phenytoin – to infantile spasms, but they are still commonly used for infant seizures. There was some disagreement at UCLA whether there really was a link, so Dr. Hussain and his team took a look at the university’s experience. They matched 50 children with nonsyndromic epilepsy who subsequently developed video-EEG confirmed infantile spasms (cases) to 50 children who also had nonsyndromic epilepsy but did not develop spasms, based on follow-up duration and age and date of epilepsy onset.

The team then looked to see what drugs they had been on; it turned out that cases and controls were about equally as likely to have been treated with any specific antiepileptic, including SCBs. Infantile spasms were substantially more likely with SCB exposure in children with spasm risk factors, which also include focal cortical dysplasia, Aicardi syndrome, and other problems (HR 7.0; 95%; CI 2.5-19.8; P less than .001). Spasms were also more likely among even low-risk children treated with SCBs, although the trend was not statistically significant.

In the end, “we wonder how many cases of infantile spasms could [have been] prevented entirely if we had avoided sodium channel blockade,” Dr. Hussain said at the annual meeting of the American Epilepsy Society.

With so many other seizure options available – levetiracetam, topiramate, and phenobarbital, to name just a few – maybe it would be best “to stay away from” SCBs entirely in “infants with any form of epilepsy,” said lead investigator Jaeden Heesch, an undergraduate researcher who worked with Dr. Hussain.

M. Alexander Otto/MDedge News

[email protected]

SOURCE: Heesch J et al. AES 2019. Abstract 2.234.

BALTIMORE – Sodium channel blocker antiepileptic drugs increase the risk of infantile spasms sevenfold in children with Down syndrome, tuberous sclerosis complex, hypoxic-ischemic encephalopathy, and other nonsyndromic epilepsy conditions with infantile spasms, according to a case-control review from the University of California, Los Angeles. “This is scary and warrants caution,” said senior investigator and pediatric neurologist Shaun Hussain, MD, a pediatric neurologist at Mattel Children’s Hospital at UCLA. Because of the findings, “we are avoiding the use of voltage-gated sodium channel blockade in any child at risk for infantile spasms. More broadly, we are avoiding [them] in any infant if there is a good alternative medication, of which there are many in most cases.”

There have been a few previous case reports linking voltage-gated sodium channel blockers (SCBs) – which include oxcarbazepine, carbamazepine, lacosamide, and phenytoin – to infantile spasms, but they are still commonly used for infant seizures. There was some disagreement at UCLA whether there really was a link, so Dr. Hussain and his team took a look at the university’s experience. They matched 50 children with nonsyndromic epilepsy who subsequently developed video-EEG confirmed infantile spasms (cases) to 50 children who also had nonsyndromic epilepsy but did not develop spasms, based on follow-up duration and age and date of epilepsy onset.

The team then looked to see what drugs they had been on; it turned out that cases and controls were about equally as likely to have been treated with any specific antiepileptic, including SCBs. Infantile spasms were substantially more likely with SCB exposure in children with spasm risk factors, which also include focal cortical dysplasia, Aicardi syndrome, and other problems (HR 7.0; 95%; CI 2.5-19.8; P less than .001). Spasms were also more likely among even low-risk children treated with SCBs, although the trend was not statistically significant.

In the end, “we wonder how many cases of infantile spasms could [have been] prevented entirely if we had avoided sodium channel blockade,” Dr. Hussain said at the annual meeting of the American Epilepsy Society.

With so many other seizure options available – levetiracetam, topiramate, and phenobarbital, to name just a few – maybe it would be best “to stay away from” SCBs entirely in “infants with any form of epilepsy,” said lead investigator Jaeden Heesch, an undergraduate researcher who worked with Dr. Hussain.

M. Alexander Otto/MDedge News

[email protected]

SOURCE: Heesch J et al. AES 2019. Abstract 2.234.

PHILADELPHIA – Obese people living in the United Kingdom who underwent bariatric surgery had a two-thirds lower rate of major cerebrovascular events than that of a matched group of obese residents who did not undergo bariatric surgery, in a retrospective study of 8,424 people followed for a mean of just over 11 years.

Mitchel L. Zoler/MDedge News

Although the cut in cerebrovascular events that linked with bariatric surgery shown by the analysis was mostly driven by a reduced rate of transient ischemic attacks, a potentially unreliable diagnosis, the results showed consistent reductions in the rates of acute ischemic strokes as well as in acute, nontraumatic intracranial hemorrhages, two other components of the combined primary endpoint, Maddalena Ardissino, MBBS, said at the American Heart Association scientific sessions.

This finding of an apparent benefit from bariatric surgery in obese patients in a large U.K. database confirms other findings from a “fast-growing” evidence base showing benefits from bariatric surgery for reducing other types of cardiovascular disease events, said Dr. Ardissino, a researcher at Imperial College, London. However, the impact of bariatric surgery specifically on cerebrovascular events had not received much attention in published studies, she noted.

Her study used data collected by the Clinical Practice Research Datalink, which has primary and secondary care health records for about 42 million U.K. residents. The researchers focused on more than 251,000 obese U.K. adults (body mass index of 30 kg/m² or greater) without a history of a cerebrovascular event who had at least 1 year of follow-up, a data file that included 4,212 adults who had undergone bariatric surgery. Their analysis matched these surgical patients with an equal number of obese adults who did not have surgery, pairing the cases and controls based on age, sex, and BMI. The resulting matched cohorts each averaged 50 years old, with a mean BMI of 40.5 kg/m².

During just over 11 years of average follow-up, the incidence of acute ischemic stroke, acute intracranial hemorrhage, subarachnoid hemorrhage, or transient ischemic attack was about 1.3% in those without bariatric surgery and about 0.4% in those who had surgery, an absolute risk reduction of 0.9 linked with surgery and a relative risk reduction of 65% that was statistically significant, Dr. Ardissino reported. All-cause mortality was about 70% lower in the group that underwent bariatric surgery compared with those who did not have surgery, a finding that confirmed prior reports. She cautioned that the analysis was limited by a relatively low number of total events, and by the small number of criteria used for cohort matching that might have left unadjusted certain potential confounders such as the level of engagement people had with their medical care.

[email protected]

SOURCE: Ardissino M. AHA 2019, Abstract 335.

PHILADELPHIA – Obese people living in the United Kingdom who underwent bariatric surgery had a two-thirds lower rate of major cerebrovascular events than that of a matched group of obese residents who did not undergo bariatric surgery, in a retrospective study of 8,424 people followed for a mean of just over 11 years.

Mitchel L. Zoler/MDedge News

Although the cut in cerebrovascular events that linked with bariatric surgery shown by the analysis was mostly driven by a reduced rate of transient ischemic attacks, a potentially unreliable diagnosis, the results showed consistent reductions in the rates of acute ischemic strokes as well as in acute, nontraumatic intracranial hemorrhages, two other components of the combined primary endpoint, Maddalena Ardissino, MBBS, said at the American Heart Association scientific sessions.

This finding of an apparent benefit from bariatric surgery in obese patients in a large U.K. database confirms other findings from a “fast-growing” evidence base showing benefits from bariatric surgery for reducing other types of cardiovascular disease events, said Dr. Ardissino, a researcher at Imperial College, London. However, the impact of bariatric surgery specifically on cerebrovascular events had not received much attention in published studies, she noted.

Her study used data collected by the Clinical Practice Research Datalink, which has primary and secondary care health records for about 42 million U.K. residents. The researchers focused on more than 251,000 obese U.K. adults (body mass index of 30 kg/m² or greater) without a history of a cerebrovascular event who had at least 1 year of follow-up, a data file that included 4,212 adults who had undergone bariatric surgery. Their analysis matched these surgical patients with an equal number of obese adults who did not have surgery, pairing the cases and controls based on age, sex, and BMI. The resulting matched cohorts each averaged 50 years old, with a mean BMI of 40.5 kg/m².

During just over 11 years of average follow-up, the incidence of acute ischemic stroke, acute intracranial hemorrhage, subarachnoid hemorrhage, or transient ischemic attack was about 1.3% in those without bariatric surgery and about 0.4% in those who had surgery, an absolute risk reduction of 0.9 linked with surgery and a relative risk reduction of 65% that was statistically significant, Dr. Ardissino reported. All-cause mortality was about 70% lower in the group that underwent bariatric surgery compared with those who did not have surgery, a finding that confirmed prior reports. She cautioned that the analysis was limited by a relatively low number of total events, and by the small number of criteria used for cohort matching that might have left unadjusted certain potential confounders such as the level of engagement people had with their medical care.

[email protected]

SOURCE: Ardissino M. AHA 2019, Abstract 335.

PHILADELPHIA – Obese people living in the United Kingdom who underwent bariatric surgery had a two-thirds lower rate of major cerebrovascular events than that of a matched group of obese residents who did not undergo bariatric surgery, in a retrospective study of 8,424 people followed for a mean of just over 11 years.

Mitchel L. Zoler/MDedge News

Although the cut in cerebrovascular events that linked with bariatric surgery shown by the analysis was mostly driven by a reduced rate of transient ischemic attacks, a potentially unreliable diagnosis, the results showed consistent reductions in the rates of acute ischemic strokes as well as in acute, nontraumatic intracranial hemorrhages, two other components of the combined primary endpoint, Maddalena Ardissino, MBBS, said at the American Heart Association scientific sessions.

This finding of an apparent benefit from bariatric surgery in obese patients in a large U.K. database confirms other findings from a “fast-growing” evidence base showing benefits from bariatric surgery for reducing other types of cardiovascular disease events, said Dr. Ardissino, a researcher at Imperial College, London. However, the impact of bariatric surgery specifically on cerebrovascular events had not received much attention in published studies, she noted.

Her study used data collected by the Clinical Practice Research Datalink, which has primary and secondary care health records for about 42 million U.K. residents. The researchers focused on more than 251,000 obese U.K. adults (body mass index of 30 kg/m² or greater) without a history of a cerebrovascular event who had at least 1 year of follow-up, a data file that included 4,212 adults who had undergone bariatric surgery. Their analysis matched these surgical patients with an equal number of obese adults who did not have surgery, pairing the cases and controls based on age, sex, and BMI. The resulting matched cohorts each averaged 50 years old, with a mean BMI of 40.5 kg/m².

During just over 11 years of average follow-up, the incidence of acute ischemic stroke, acute intracranial hemorrhage, subarachnoid hemorrhage, or transient ischemic attack was about 1.3% in those without bariatric surgery and about 0.4% in those who had surgery, an absolute risk reduction of 0.9 linked with surgery and a relative risk reduction of 65% that was statistically significant, Dr. Ardissino reported. All-cause mortality was about 70% lower in the group that underwent bariatric surgery compared with those who did not have surgery, a finding that confirmed prior reports. She cautioned that the analysis was limited by a relatively low number of total events, and by the small number of criteria used for cohort matching that might have left unadjusted certain potential confounders such as the level of engagement people had with their medical care.

[email protected]

SOURCE: Ardissino M. AHA 2019, Abstract 335.

BALTIMORE – The effect of caffeine on seizures may be dose dependent, according to research presented at the annual meeting of the American Epilepsy Society. Moderate doses of caffeine may benefit patients with epilepsy, whereas high doses – four cups of coffee per day or more – may increase seizure susceptibility, said Julie Bourgeois-Vionnet, MD, of the department of functional neurology and epileptology at Hospices Civils de Lyon in France.

Jake Remaly/MDedge News

In rodent model studies, caffeine has been found in general to increase seizure susceptibility but with variable results according to dose and route of administration, but other studies of chronic low-dose exposure to caffeine have reported protective effects against seizures and sudden unexpected death in epilepsy (SUDEP; Epilepsy Behav. 2018 Mar;80:37-47). In patients, however, the relationship between caffeine consumption and seizure frequency has been less clear.

To examine the relationship between caffeine consumption and seizure frequency in patients with drug-resistant epilepsy, Dr. Bourgeois-Vionnet and colleagues analyzed data patients in the Safety of Antiepileptic Withdrawal in Long Term Video-EEG Monitoring (SAVE) study. This ongoing, multicenter, open-label trial is evaluating the management of antiepileptic drugs withdrawal during long-term monitoring in patients with drug-resistant focal epilepsy.

For the present analysis, the researchers examined data from 620 adults who were included in the SAVE study between 2016 and 2018 and had information available about coffee consumption and seizure frequency, including seizure frequency during the previous 3 months and number of focal seizure evolving to generalized tonic-clonic seizures (secondary generalized tonic-clonic seizures [sGTCS]) during the past year. Patients provided information about coffee consumption via a standardized questionnaire.

The investigators classified caffeine consumption as none, rare (less than 1 cup/week to up to 3 cups/week), moderate (between 4 cups/week and 3 cups/day) and high (more than 4 cups/day). The researchers evaluated risk of SUDEP using the revised SUDEP-7 inventory.

The patients had an average age of 36.2 years and an average duration of epilepsy of 18.1 years. In the 3 months preceding study inclusion, the median seizure frequency of any type was 4.33 per month. In all, 217 patients reported sGTCS in the past year.

Overall, 194 patients reported no coffee consumption, 149 reported rare coffee consumption, 177 moderate consumption, and 100 high consumption. The revised SUDEP-7 inventory was available for 607 patients, and the median score was 3.0.

Patients with moderate coffee consumption were more likely to not have any sGTCS (73.4%), compared with patients with no coffee consumption (64.4%), rare consumption (61.7%), and high consumption (56%). Likewise, patients with moderate coffee consumption were less likely to have more than three sGTCS per year (19.2%), compared with patients no coffee consumption (28.9%), rare consumption (24.8%), and high consumption (30%).

“There was no relation between caffeine consumption and seizure frequency of any type,” Dr. Bourgeois-Vionnet and colleagues reported. “However, we observed a bimodal association between frequency of sGTCS and coffee consumption. In contrast, no significant association was observed between score of the SUDEP-7 inventory and level of caffeine consumption.”

While these findings still need to be confirmed in prospective studies, they suggest possible guidance for patients, Dr. Bourgeois-Vionnet said. “They are allowed to drink coffee, but maybe avoid high doses,” she said.

The study was funded by the French Ministry of Health. The researchers had no disclosures.
 

[email protected]

SOURCE: Bourgeois-Vionnet J. AES 2019, Abstract 2.141.

BALTIMORE – The effect of caffeine on seizures may be dose dependent, according to research presented at the annual meeting of the American Epilepsy Society. Moderate doses of caffeine may benefit patients with epilepsy, whereas high doses – four cups of coffee per day or more – may increase seizure susceptibility, said Julie Bourgeois-Vionnet, MD, of the department of functional neurology and epileptology at Hospices Civils de Lyon in France.

Jake Remaly/MDedge News

In rodent model studies, caffeine has been found in general to increase seizure susceptibility but with variable results according to dose and route of administration, but other studies of chronic low-dose exposure to caffeine have reported protective effects against seizures and sudden unexpected death in epilepsy (SUDEP; Epilepsy Behav. 2018 Mar;80:37-47). In patients, however, the relationship between caffeine consumption and seizure frequency has been less clear.

To examine the relationship between caffeine consumption and seizure frequency in patients with drug-resistant epilepsy, Dr. Bourgeois-Vionnet and colleagues analyzed data patients in the Safety of Antiepileptic Withdrawal in Long Term Video-EEG Monitoring (SAVE) study. This ongoing, multicenter, open-label trial is evaluating the management of antiepileptic drugs withdrawal during long-term monitoring in patients with drug-resistant focal epilepsy.

For the present analysis, the researchers examined data from 620 adults who were included in the SAVE study between 2016 and 2018 and had information available about coffee consumption and seizure frequency, including seizure frequency during the previous 3 months and number of focal seizure evolving to generalized tonic-clonic seizures (secondary generalized tonic-clonic seizures [sGTCS]) during the past year. Patients provided information about coffee consumption via a standardized questionnaire.

The investigators classified caffeine consumption as none, rare (less than 1 cup/week to up to 3 cups/week), moderate (between 4 cups/week and 3 cups/day) and high (more than 4 cups/day). The researchers evaluated risk of SUDEP using the revised SUDEP-7 inventory.

The patients had an average age of 36.2 years and an average duration of epilepsy of 18.1 years. In the 3 months preceding study inclusion, the median seizure frequency of any type was 4.33 per month. In all, 217 patients reported sGTCS in the past year.

Overall, 194 patients reported no coffee consumption, 149 reported rare coffee consumption, 177 moderate consumption, and 100 high consumption. The revised SUDEP-7 inventory was available for 607 patients, and the median score was 3.0.

Patients with moderate coffee consumption were more likely to not have any sGTCS (73.4%), compared with patients with no coffee consumption (64.4%), rare consumption (61.7%), and high consumption (56%). Likewise, patients with moderate coffee consumption were less likely to have more than three sGTCS per year (19.2%), compared with patients no coffee consumption (28.9%), rare consumption (24.8%), and high consumption (30%).

“There was no relation between caffeine consumption and seizure frequency of any type,” Dr. Bourgeois-Vionnet and colleagues reported. “However, we observed a bimodal association between frequency of sGTCS and coffee consumption. In contrast, no significant association was observed between score of the SUDEP-7 inventory and level of caffeine consumption.”

While these findings still need to be confirmed in prospective studies, they suggest possible guidance for patients, Dr. Bourgeois-Vionnet said. “They are allowed to drink coffee, but maybe avoid high doses,” she said.

The study was funded by the French Ministry of Health. The researchers had no disclosures.
 

[email protected]

SOURCE: Bourgeois-Vionnet J. AES 2019, Abstract 2.141.

BALTIMORE – The effect of caffeine on seizures may be dose dependent, according to research presented at the annual meeting of the American Epilepsy Society. Moderate doses of caffeine may benefit patients with epilepsy, whereas high doses – four cups of coffee per day or more – may increase seizure susceptibility, said Julie Bourgeois-Vionnet, MD, of the department of functional neurology and epileptology at Hospices Civils de Lyon in France.

Jake Remaly/MDedge News

In rodent model studies, caffeine has been found in general to increase seizure susceptibility but with variable results according to dose and route of administration, but other studies of chronic low-dose exposure to caffeine have reported protective effects against seizures and sudden unexpected death in epilepsy (SUDEP; Epilepsy Behav. 2018 Mar;80:37-47). In patients, however, the relationship between caffeine consumption and seizure frequency has been less clear.

To examine the relationship between caffeine consumption and seizure frequency in patients with drug-resistant epilepsy, Dr. Bourgeois-Vionnet and colleagues analyzed data patients in the Safety of Antiepileptic Withdrawal in Long Term Video-EEG Monitoring (SAVE) study. This ongoing, multicenter, open-label trial is evaluating the management of antiepileptic drugs withdrawal during long-term monitoring in patients with drug-resistant focal epilepsy.

For the present analysis, the researchers examined data from 620 adults who were included in the SAVE study between 2016 and 2018 and had information available about coffee consumption and seizure frequency, including seizure frequency during the previous 3 months and number of focal seizure evolving to generalized tonic-clonic seizures (secondary generalized tonic-clonic seizures [sGTCS]) during the past year. Patients provided information about coffee consumption via a standardized questionnaire.

The investigators classified caffeine consumption as none, rare (less than 1 cup/week to up to 3 cups/week), moderate (between 4 cups/week and 3 cups/day) and high (more than 4 cups/day). The researchers evaluated risk of SUDEP using the revised SUDEP-7 inventory.

The patients had an average age of 36.2 years and an average duration of epilepsy of 18.1 years. In the 3 months preceding study inclusion, the median seizure frequency of any type was 4.33 per month. In all, 217 patients reported sGTCS in the past year.

Overall, 194 patients reported no coffee consumption, 149 reported rare coffee consumption, 177 moderate consumption, and 100 high consumption. The revised SUDEP-7 inventory was available for 607 patients, and the median score was 3.0.

Patients with moderate coffee consumption were more likely to not have any sGTCS (73.4%), compared with patients with no coffee consumption (64.4%), rare consumption (61.7%), and high consumption (56%). Likewise, patients with moderate coffee consumption were less likely to have more than three sGTCS per year (19.2%), compared with patients no coffee consumption (28.9%), rare consumption (24.8%), and high consumption (30%).

“There was no relation between caffeine consumption and seizure frequency of any type,” Dr. Bourgeois-Vionnet and colleagues reported. “However, we observed a bimodal association between frequency of sGTCS and coffee consumption. In contrast, no significant association was observed between score of the SUDEP-7 inventory and level of caffeine consumption.”

While these findings still need to be confirmed in prospective studies, they suggest possible guidance for patients, Dr. Bourgeois-Vionnet said. “They are allowed to drink coffee, but maybe avoid high doses,” she said.

The study was funded by the French Ministry of Health. The researchers had no disclosures.
 

[email protected]

SOURCE: Bourgeois-Vionnet J. AES 2019, Abstract 2.141.

SAN DIEGO – Addiction specialists have a message for American policymakers who are rushing to create laws to allow the use of medical and recreational marijuana: You’re doing it wrong, but we know how you can do it right.

Smithore

“We can have spirited debates on these policies, recreational, medical decriminalization, etc. But we can’t argue how we’ve done a poor job implementing these policies in the United States,” psychiatrist Kevin P. Hill, MD, of Harvard Medical School, Boston, said in a symposium about cannabis policy at the annual meeting of the American Academy of Addiction Psychiatry.

The AAAP is proposing a “model state law” regarding cannabis. Among other things, the proposal urges states to:

• Ban recreational use of cannabis until the age of 21, and perhaps even until 25.
• Not denote psychiatric indications such as posttraumatic stress disorder, anxiety, and depression as qualifying conditions for the use of medical marijuana.
• Educate the public about potential harms of cannabis.
• Provide state-level regulation that includes funding of high-grade analytic equipment to test cannabis.
• Maintain a public registry that reports annually on adverse outcomes.

Research suggests that marijuana use has spiked in recent years, Dr. Hill said. Meanwhile, states have dramatically broadened the legality of marijuana. According to the National Conference of State Legislatures, 33 states and the District of Columbia allow the medical use of marijuana. Of those, 11 states and the District of Columbia also allow the adult use of recreational marijuana. Several other states allow access to cannabidiol (CBD)/low-THC products in some cases (www.ncsl.org/research/health/state-medical-marijuana-laws.aspx).

The problem, Dr. Hill said, is that there’s “a big gap between what the science says and what the laws are saying, unfortunately. So we’re in this precarious spot.”

He pointed to his own 2015 review of cannabinoid studies that found high-quality evidence for an effect for just three conditions – chronic pain, neuropathic pain, and spasticity associated with multiple sclerosis. The study notes that Food and Drug Administration–approved cannabinoids are also available to treat nausea and vomiting linked to chemotherapy and to boost appetite in patients with wasting disease. (JAMA. 2015 Jun 23-30;313(24):2474-83).

However, states have listed dozens of conditions – 53 overall – as qualifying conditions for the use of medical marijuana, Dr. Hill said. And, he said, “the reality is that a lot of people who are using medical cannabis don’t have any of these conditions,” he said.

Researchers at the symposium focused on the use of cannabis as a treatment for addiction and other psychiatric illnesses.

Four states have legalized the use of cannabis in patients with opioid use disorder, said cannabis researcher Ziva D. Cooper, PhD, of the University of California, Los Angeles, who spoke at the symposium. But can cannabis actually reduce opioid use? Preliminary clinical data suggest THC could reduce opioid use, Dr. Cooper said, while population and state-level research is mixed.

What about other mental health disorders? Posttraumatic stress disorder is commonly listed as a qualifying condition for medical marijuana use in state laws. And some states, like California, give physicians wide leeway in recommending marijuana use for patients with conditions that aren’t listed in the law.

However, symposium speaker and psychiatrist Frances R. Levin, MD, of New York State Psychiatric Institute, pointed to a 2019 review that suggests “there is scarce evidence to suggest that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, posttraumatic stress disorder, or psychosis” (Lancet Psychiatry. 2019 Dec;6[12]:995-1010). 

What now? The AAAP hopes lawmakers will pay attention to its proposed model state law, which will be published soon in the association’s journal, the American Journal on Addictions.

SAN DIEGO – Addiction specialists have a message for American policymakers who are rushing to create laws to allow the use of medical and recreational marijuana: You’re doing it wrong, but we know how you can do it right.

Smithore

“We can have spirited debates on these policies, recreational, medical decriminalization, etc. But we can’t argue how we’ve done a poor job implementing these policies in the United States,” psychiatrist Kevin P. Hill, MD, of Harvard Medical School, Boston, said in a symposium about cannabis policy at the annual meeting of the American Academy of Addiction Psychiatry.

The AAAP is proposing a “model state law” regarding cannabis. Among other things, the proposal urges states to:

• Ban recreational use of cannabis until the age of 21, and perhaps even until 25.
• Not denote psychiatric indications such as posttraumatic stress disorder, anxiety, and depression as qualifying conditions for the use of medical marijuana.
• Educate the public about potential harms of cannabis.
• Provide state-level regulation that includes funding of high-grade analytic equipment to test cannabis.
• Maintain a public registry that reports annually on adverse outcomes.

Research suggests that marijuana use has spiked in recent years, Dr. Hill said. Meanwhile, states have dramatically broadened the legality of marijuana. According to the National Conference of State Legislatures, 33 states and the District of Columbia allow the medical use of marijuana. Of those, 11 states and the District of Columbia also allow the adult use of recreational marijuana. Several other states allow access to cannabidiol (CBD)/low-THC products in some cases (www.ncsl.org/research/health/state-medical-marijuana-laws.aspx).

The problem, Dr. Hill said, is that there’s “a big gap between what the science says and what the laws are saying, unfortunately. So we’re in this precarious spot.”

He pointed to his own 2015 review of cannabinoid studies that found high-quality evidence for an effect for just three conditions – chronic pain, neuropathic pain, and spasticity associated with multiple sclerosis. The study notes that Food and Drug Administration–approved cannabinoids are also available to treat nausea and vomiting linked to chemotherapy and to boost appetite in patients with wasting disease. (JAMA. 2015 Jun 23-30;313(24):2474-83).

However, states have listed dozens of conditions – 53 overall – as qualifying conditions for the use of medical marijuana, Dr. Hill said. And, he said, “the reality is that a lot of people who are using medical cannabis don’t have any of these conditions,” he said.

Researchers at the symposium focused on the use of cannabis as a treatment for addiction and other psychiatric illnesses.

Four states have legalized the use of cannabis in patients with opioid use disorder, said cannabis researcher Ziva D. Cooper, PhD, of the University of California, Los Angeles, who spoke at the symposium. But can cannabis actually reduce opioid use? Preliminary clinical data suggest THC could reduce opioid use, Dr. Cooper said, while population and state-level research is mixed.

What about other mental health disorders? Posttraumatic stress disorder is commonly listed as a qualifying condition for medical marijuana use in state laws. And some states, like California, give physicians wide leeway in recommending marijuana use for patients with conditions that aren’t listed in the law.

However, symposium speaker and psychiatrist Frances R. Levin, MD, of New York State Psychiatric Institute, pointed to a 2019 review that suggests “there is scarce evidence to suggest that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, posttraumatic stress disorder, or psychosis” (Lancet Psychiatry. 2019 Dec;6[12]:995-1010). 

What now? The AAAP hopes lawmakers will pay attention to its proposed model state law, which will be published soon in the association’s journal, the American Journal on Addictions.

SAN DIEGO – Addiction specialists have a message for American policymakers who are rushing to create laws to allow the use of medical and recreational marijuana: You’re doing it wrong, but we know how you can do it right.

Smithore

“We can have spirited debates on these policies, recreational, medical decriminalization, etc. But we can’t argue how we’ve done a poor job implementing these policies in the United States,” psychiatrist Kevin P. Hill, MD, of Harvard Medical School, Boston, said in a symposium about cannabis policy at the annual meeting of the American Academy of Addiction Psychiatry.

The AAAP is proposing a “model state law” regarding cannabis. Among other things, the proposal urges states to:

• Ban recreational use of cannabis until the age of 21, and perhaps even until 25.
• Not denote psychiatric indications such as posttraumatic stress disorder, anxiety, and depression as qualifying conditions for the use of medical marijuana.
• Educate the public about potential harms of cannabis.
• Provide state-level regulation that includes funding of high-grade analytic equipment to test cannabis.
• Maintain a public registry that reports annually on adverse outcomes.

Research suggests that marijuana use has spiked in recent years, Dr. Hill said. Meanwhile, states have dramatically broadened the legality of marijuana. According to the National Conference of State Legislatures, 33 states and the District of Columbia allow the medical use of marijuana. Of those, 11 states and the District of Columbia also allow the adult use of recreational marijuana. Several other states allow access to cannabidiol (CBD)/low-THC products in some cases (www.ncsl.org/research/health/state-medical-marijuana-laws.aspx).

The problem, Dr. Hill said, is that there’s “a big gap between what the science says and what the laws are saying, unfortunately. So we’re in this precarious spot.”

He pointed to his own 2015 review of cannabinoid studies that found high-quality evidence for an effect for just three conditions – chronic pain, neuropathic pain, and spasticity associated with multiple sclerosis. The study notes that Food and Drug Administration–approved cannabinoids are also available to treat nausea and vomiting linked to chemotherapy and to boost appetite in patients with wasting disease. (JAMA. 2015 Jun 23-30;313(24):2474-83).

However, states have listed dozens of conditions – 53 overall – as qualifying conditions for the use of medical marijuana, Dr. Hill said. And, he said, “the reality is that a lot of people who are using medical cannabis don’t have any of these conditions,” he said.

Researchers at the symposium focused on the use of cannabis as a treatment for addiction and other psychiatric illnesses.

Four states have legalized the use of cannabis in patients with opioid use disorder, said cannabis researcher Ziva D. Cooper, PhD, of the University of California, Los Angeles, who spoke at the symposium. But can cannabis actually reduce opioid use? Preliminary clinical data suggest THC could reduce opioid use, Dr. Cooper said, while population and state-level research is mixed.

What about other mental health disorders? Posttraumatic stress disorder is commonly listed as a qualifying condition for medical marijuana use in state laws. And some states, like California, give physicians wide leeway in recommending marijuana use for patients with conditions that aren’t listed in the law.

However, symposium speaker and psychiatrist Frances R. Levin, MD, of New York State Psychiatric Institute, pointed to a 2019 review that suggests “there is scarce evidence to suggest that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, posttraumatic stress disorder, or psychosis” (Lancet Psychiatry. 2019 Dec;6[12]:995-1010). 

What now? The AAAP hopes lawmakers will pay attention to its proposed model state law, which will be published soon in the association’s journal, the American Journal on Addictions.

BALTIMORE – In a review of 43 temporal lobe epilepsy patients at Yale University in New Haven, Conn., anteromedial temporal resection (AMTR) failed in every case in which initial ictal rhythm on scalp EEG spread beyond the medial temporal lobe to other brain regions within 10 seconds.

Among the 33 patients who had no spread on preoperative scalp EEG or who spread in 10 or more seconds, 31 (94%) had a good outcome, meaning they were seizure free or had only auras after AMTR. The findings could mean that scalp EEG can predict surgery outcome.

AMTR works in the majority of patients with refractory temporal lobe epilepsy, but about 10-20% continue to have seizures. Senior investigator Pue Farooque, DO, from Yale University wanted to find a way to identify patients likely to fail surgery beforehand to help counsel patients on what to expect and also to know when other treatment options might be a better bet.

“If you see seizures are spreading quickly to another area, like the frontal lobe or the temporal neocortex, you could implant RNS [responsive neurostimulation]” instead of doing an ATMR, “and that might improve your outcomes,” she said at the American Epilepsy Society’s annual meeting.

The findings are essentially the same as when the group used intracranial EEG to detect fast spread in a previous report, but scalp EEG is noninvasive and allows for easy preoperative assessment (JAMA Neurol. 2019 Apr 1;76[4]:462-9).

The team also found in their new study that diffuse hypometabolism in the entire temporal lobe on quantitative PET also predicted poor ATMR outcomes (P less than .001), but Dr. Farooque said more work is needed to quantify the finding. The investigators also plan to assess the predictive value of resting functional MRI.

The take home, she said, is that “we can do better” with epilepsy surgery, and “there are noninvasive markers we can use to help guide us.”

It’s unclear why more rapid seizure spread would predict AMTR failure. In the earlier study with intracranial EEG, the investigators said “the results are best explained by attributing epileptogenic potential to sites of early seizure spread that were not included in resection. This mechanism of failure implies that a distributed epileptogenic network rather than a single epileptogenic focus may underlie surgically refractory epilepsy.”

Patients in the new report had epilepsy for a mean of 24.4 years, and 25 (58%) were women; 30 cases (69%) were lesional, and follow-up was at least a year. The contralateral or lateralized seizure spread ranged from 1 to 63 seconds, with a mean of 18.5 seconds. Among patients who failed AMTR, seizure spread occurred at a mean of 7.1 seconds.

Electrographic pattern at onset and location of interictal epileptiform discharges did not predict outcome

There was no industry funding, and Dr. Farooque didn’t have any relevant disclosures.

[email protected]

SOURCE: Chiari J et al. AES 2019, Abstract 1.36.

BALTIMORE – In a review of 43 temporal lobe epilepsy patients at Yale University in New Haven, Conn., anteromedial temporal resection (AMTR) failed in every case in which initial ictal rhythm on scalp EEG spread beyond the medial temporal lobe to other brain regions within 10 seconds.

Among the 33 patients who had no spread on preoperative scalp EEG or who spread in 10 or more seconds, 31 (94%) had a good outcome, meaning they were seizure free or had only auras after AMTR. The findings could mean that scalp EEG can predict surgery outcome.

AMTR works in the majority of patients with refractory temporal lobe epilepsy, but about 10-20% continue to have seizures. Senior investigator Pue Farooque, DO, from Yale University wanted to find a way to identify patients likely to fail surgery beforehand to help counsel patients on what to expect and also to know when other treatment options might be a better bet.

“If you see seizures are spreading quickly to another area, like the frontal lobe or the temporal neocortex, you could implant RNS [responsive neurostimulation]” instead of doing an ATMR, “and that might improve your outcomes,” she said at the American Epilepsy Society’s annual meeting.

The findings are essentially the same as when the group used intracranial EEG to detect fast spread in a previous report, but scalp EEG is noninvasive and allows for easy preoperative assessment (JAMA Neurol. 2019 Apr 1;76[4]:462-9).

The team also found in their new study that diffuse hypometabolism in the entire temporal lobe on quantitative PET also predicted poor ATMR outcomes (P less than .001), but Dr. Farooque said more work is needed to quantify the finding. The investigators also plan to assess the predictive value of resting functional MRI.

The take home, she said, is that “we can do better” with epilepsy surgery, and “there are noninvasive markers we can use to help guide us.”

It’s unclear why more rapid seizure spread would predict AMTR failure. In the earlier study with intracranial EEG, the investigators said “the results are best explained by attributing epileptogenic potential to sites of early seizure spread that were not included in resection. This mechanism of failure implies that a distributed epileptogenic network rather than a single epileptogenic focus may underlie surgically refractory epilepsy.”

Patients in the new report had epilepsy for a mean of 24.4 years, and 25 (58%) were women; 30 cases (69%) were lesional, and follow-up was at least a year. The contralateral or lateralized seizure spread ranged from 1 to 63 seconds, with a mean of 18.5 seconds. Among patients who failed AMTR, seizure spread occurred at a mean of 7.1 seconds.

Electrographic pattern at onset and location of interictal epileptiform discharges did not predict outcome

There was no industry funding, and Dr. Farooque didn’t have any relevant disclosures.

[email protected]

SOURCE: Chiari J et al. AES 2019, Abstract 1.36.

BALTIMORE – In a review of 43 temporal lobe epilepsy patients at Yale University in New Haven, Conn., anteromedial temporal resection (AMTR) failed in every case in which initial ictal rhythm on scalp EEG spread beyond the medial temporal lobe to other brain regions within 10 seconds.

Among the 33 patients who had no spread on preoperative scalp EEG or who spread in 10 or more seconds, 31 (94%) had a good outcome, meaning they were seizure free or had only auras after AMTR. The findings could mean that scalp EEG can predict surgery outcome.

AMTR works in the majority of patients with refractory temporal lobe epilepsy, but about 10-20% continue to have seizures. Senior investigator Pue Farooque, DO, from Yale University wanted to find a way to identify patients likely to fail surgery beforehand to help counsel patients on what to expect and also to know when other treatment options might be a better bet.

“If you see seizures are spreading quickly to another area, like the frontal lobe or the temporal neocortex, you could implant RNS [responsive neurostimulation]” instead of doing an ATMR, “and that might improve your outcomes,” she said at the American Epilepsy Society’s annual meeting.

The findings are essentially the same as when the group used intracranial EEG to detect fast spread in a previous report, but scalp EEG is noninvasive and allows for easy preoperative assessment (JAMA Neurol. 2019 Apr 1;76[4]:462-9).

The team also found in their new study that diffuse hypometabolism in the entire temporal lobe on quantitative PET also predicted poor ATMR outcomes (P less than .001), but Dr. Farooque said more work is needed to quantify the finding. The investigators also plan to assess the predictive value of resting functional MRI.

The take home, she said, is that “we can do better” with epilepsy surgery, and “there are noninvasive markers we can use to help guide us.”

It’s unclear why more rapid seizure spread would predict AMTR failure. In the earlier study with intracranial EEG, the investigators said “the results are best explained by attributing epileptogenic potential to sites of early seizure spread that were not included in resection. This mechanism of failure implies that a distributed epileptogenic network rather than a single epileptogenic focus may underlie surgically refractory epilepsy.”

Patients in the new report had epilepsy for a mean of 24.4 years, and 25 (58%) were women; 30 cases (69%) were lesional, and follow-up was at least a year. The contralateral or lateralized seizure spread ranged from 1 to 63 seconds, with a mean of 18.5 seconds. Among patients who failed AMTR, seizure spread occurred at a mean of 7.1 seconds.

Electrographic pattern at onset and location of interictal epileptiform discharges did not predict outcome

There was no industry funding, and Dr. Farooque didn’t have any relevant disclosures.

[email protected]

SOURCE: Chiari J et al. AES 2019, Abstract 1.36.