User login
Positive Results From Phase 2 Trial Support Potential New Option for Control of CIDP
DENVER — , according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.
“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.
Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.
ADHERE Called Largest CIDP Trial to Date
In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.
After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.
The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,
The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.
The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.
There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
aINCAT Provided Primary Endpoint for CIDP Trial
For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.
By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.
When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.
In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.
On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
E-PH20 Is Characterized as Well Tolerated
Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.
“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.
The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.
There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.
“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.
Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.
Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.
DENVER — , according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.
“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.
Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.
ADHERE Called Largest CIDP Trial to Date
In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.
After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.
The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,
The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.
The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.
There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
aINCAT Provided Primary Endpoint for CIDP Trial
For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.
By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.
When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.
In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.
On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
E-PH20 Is Characterized as Well Tolerated
Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.
“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.
The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.
There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.
“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.
Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.
Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.
DENVER — , according to the results of a phase 2 multinational trial, which were reported at the 2024 annual meeting of the American Academy of Neurology.
“Regardless of prior therapy for CIDP, efgartigimod PH20 was associated with a rapid clinical improvement, and clinical responses have been maintained out to 48 weeks,” said Jeffrey A. Allen, MD, an associate professor of neurology, University of Minnesota, Minneapolis.
Efgartigimod, which reduces circulating IgG immunoglobulin, has been available for the treatment of myasthenia gravis since 2021. In a new trial, called ADHERE, the combination of efgartigimod and rHuPH20 (E-PH20) was tested for CIDP, the most common of the chronic immune-mediated inflammatory polyneuropathies.
ADHERE Called Largest CIDP Trial to Date
In this study, which Dr. Allen called the largest randomized controlled trial ever performed with a CIDP treatment, a run-in stage was required for those candidates who were already on treatment. When these patients went off treatment during this 12-week run-in, clinical deterioration was required to advance to the first of two stages of the trial. Patients with symptomatic CIDP but off treatment at the time of enrollment did not participate in the run-in.
After the run-in, patients who advanced to stage A received 1000 mg of E-PH20 open label for 12 weeks. Of those on treatment prior to the run-in, about half were receiving intravenous immunoglobulins (IVIg). Almost all the remainder had been receiving corticosteroids. About 30% had been off treatment and entered stage A without participating in the run in.
The primary endpoint of stage A was the percentage of patients with evidence of clinical improvement (ECI). Patients who participated in the run-in were allowed to resume their prior treatment for stage A and the subsequent blinded stage B. Stage A was event driven so that it was closed once 88 events were reached,
The ECI endpoint was met by 66.5% of the patients, who thereby met eligibility for the randomized stage B. As the study design excluded those who achieved clinical improvement after the 88-event limit was reached, they were not included among responders. Had they been included, Dr. Allen said that the primary endpoint of stage A would have been reached by 70.4%.
The patterns of improvement in stage A were similar across type of prior CIDP treatment, including no treatment, according to Dr. Allen, who noted that 39.8% of those enrolled in stage A met the primary endpoint within 4 weeks.
There were 322 patients in stage A. Of these, 211 enrolled in stage B. They were randomized in a 1:1 ratio to 1000 mg of E-PH20 or placebo administered weekly by subcutaneous injection. Of those eligible for stage B, 40% had not participated in the run-in.
aINCAT Provided Primary Endpoint for CIDP Trial
For stage B, the primary endpoint was time from baseline to a clinically meaningful limitation of activity. This was evaluated with the adjusted inflammatory neuropathy cause and treatment (aINCAT) disability score.
By the end of 48 weeks of treatment, 27.9% had relapsed on E-PH20 according to the aiNCAT disability score versus 53.6% on those on placebo. By hazard ratio (HR 0.39), the active treatment arm was associated with a highly significant 61% (P = .000039) greater likelihood of avoiding relapse.
When stratified by a background of no therapy, IVIg, subcutaneous immunoglobulins (SCIg), or corticosteroids, all groups in the active treatment arm did better in stage B than any group in the placebo arm, according to Dr. Allen.
In the 48-week deterioration curves, sustained control was observed among responders out to the end of controlled study. Although there appeared to be numerical advantage for those on both E-PH20 and corticosteroids, E-PH20 arms with concomitant IVIg, SCIg, or no treatment also showed sustained control without significant differences between them.
On functional aINCAT scores, 80.9% achieved at least a 1-point improvement. The improvement was at least 2 points in 42.7%, at least 3 points in 28.2%, and at least 4 points in 11.8%.
E-PH20 Is Characterized as Well Tolerated
Injection site erythema (5.4% vs 0%) and injection site bruising (5.4% vs 0.9%) were more common on E-PH20 than placebo, but there was no difference in serious adverse events, and events possibly related to active treatment, such as headache (3.6% vs. 1.8%) were considered to be of mild to moderate severity.
“The safety profile of efgartigimod plus PH20 was consistent with the safety profile of efgartigimod in other autoimmune diseases,” Dr. Allen said.
The weekly subcutaneous injection can be administered within 90 seconds or less, Dr. Allen said. He called this drug a potential “new therapeutic option to reduce treatment burden in patients with CIDP” if it is approved.
There is a need for new options, according to Brett M. Morrison, MD, PhD, associate professor of neurology at the Johns Hopkins School of Medicine, Baltimore, and an expert in neuromuscular disorders. Dr. Morrison was not involved in the study.
“Although there are three currently approved treatments — steroids, IVIg, and plasmapheresis, at least 20% of CIDP patients have minimal or no response” to any of these, Dr. Morrison said. He added that many of those who do respond to standard therapies have a substantial side effect burden that has created a need for alternatives.
Based on the data presented so far, which suggest substantial efficacy and a favorable safety profile, efgartigimod, if and when it becomes available, “would be an important new treatment for CIDP,” according to Dr. Morrison.
Dr. Allen has financial relationships with more than 10 pharmaceutical companies, including Argenx, which provided funding for the ACHIEVE trial. Dr. Morrison reported no potential conflicts of interest.
FROM AAN 2024
Pediatric Patients With MS May Do Best on High-Efficacy DMTs
DENVER — Patients with pediatric-onset multiple sclerosis (POMS) are often prescribed low-efficacy disease-modifying therapies (DMTs), but a new retrospective analysis suggests that, like adults, this patient population may benefit from early treatment with high-efficacy DMTs.
“I think it’s very important to highlight that we are seeing that traditionally, kids are just started on lower-efficacy treatments and they keep relapsing. If we can show that when they get transitioned to high-efficacy treatments, the relapses are lessening, I’m hoping that can then push for better clinical trials with pediatric patients included,” said Frederick Bassal, DO, who presented the study during a poster session at the 2024 annual meeting of the American Academy of Neurology. He is a pediatric neurologist at University of California, Davis.
The first line for POMS is generally low-efficacy DMTs like interferon-beta and glatiramer acetate, but these medications may not effectively control disease progression, according to the study authors, and this could lead to pediatric patients being changed to more potent therapies. That can include moderate-efficacy drugs like S1P inhibitors and fumarates, or high-efficacy DMTS such as B cell depletors and alpha 4 integrin receptor antibodies.
Treatment Strategies
“Right now what we’re seeing is the conservative approach — starting low and working up with the younger and adolescent patients. I’m speculating, and I want to look more into it. Is [it maybe] because of insurance approval?” said study coauthor Amara Miller, a medical student at the University of Arizona College of Medicine in Phoenix.
The findings aren’t surprising, according to Barbara Giesser, MD, who was asked to comment on the study. “It is in line with what we think we know about people with adult MS — that if you start early on with a more effective therapy, you tend to have better outcomes,” said Dr. Giesser, director of the MS program at the Pacific Neuroscience Institute.
Another reason to consider higher-efficacy DMTs is that children with MS can have cognitive problems and delays. “There’s a suggestion that if you treat with highly-effective DMT that you might be able to abrogate some of that,” said Dr. Giesser.
Among the approximately two dozen FDA-approved disease-modifying therapies for MS, only fingolimod (Gilenya, Novartis) is approved for children and adolescents. “All of the others are used off label, but I think perhaps, if you have more studies that [show] that children do better if you treat with more effective therapies early on, perhaps we might see more on-label indications for use in a pediatric population,” said Dr. Giesser.
The finding that obesity was associated with a higher likelihood of having multiple therapies is also interesting, she said. “We’re beginning to see that obesity in adults as well seems to portend less favorable neurologic outcomes.”
Study Methodology
The researchers analyzed data from 135 POMS patients between 2012 and 2023.
The mean age of participants was 15 years, 60% were female, and 120 of 135 were White, while 76 were of Hispanic ethnicity. Overweight and obesity were common, with 36 and 43 participants in each category. The initial therapy was a low-efficacy DMT in 23.0% of participants, moderate-efficacy in 37.0%, and high-efficacy in 24.4%, while 1.5% received some other kind of medication and 14.1% received no medication. The annualized relapse rate was 0.932, and the mean EDSS score was 0.88.
Patients who underwent three or medication changes had lower EDSS scores than those who underwent zero to 2 (P = .00607).
Over the course of the study, the percentage of patients who received high-efficacy DMTs rose from 25.9% to 48.9%, largely due to changes in medication. Of those initially prescribed low-efficacy DMTs, 77.4% were eventually switched to high-efficacy DMTs.
Every patient who underwent three or more medication changes was initially prescribed a low-efficacy DMT.
Patients started on low-efficacy drugs had a mean of 1.42 medication changes, compared with 0.94 in the moderate-efficacy group and 0.51 in the high-efficacy group. The reasons for changing from the first medication included relapse (36), side effects (11), patient choice or compliance (8), and pregnancy (2).
Patients 10 years or younger were more likely to be initially prescribed a low-efficacy therapy (odds ratio [OR], 5.72; P = .0366), while older patients were more likely to be prescribed moderate- or high-efficacy therapies (OR, 14.44; P = .0012).
There were more total medication changes in the low-efficacy group than the high initial DMT group (P = .000305).
Asked what advice they would give to physicians treating POMS patients, Ms. Miller suggested a top-down approach. “We want to look at if maybe we can start with higher efficacy DMT’s and maybe titering it down. That may be an option,” said Ms. Miller.
Dr. Bassal highlighted the importance of shared decision-making. “We want to go over the options, that we recommend higher-efficacy [DMTs] for these reasons. But every individual is different. And there may be fears that are very reasonable that families have. I think in those cases, it’s also reasonable to make a shared decision. And if that means going with something like an oral, moderate- to lower-efficacy [therapy], that’s okay, because compliance is key, and if you start something where the family is afraid of side effects, or there are side effects, then you kind of lost that opportunity,” he said.
Dr. Bassal, Dr. Giesser, and Ms. Miller have no relevant financial disclosures.
DENVER — Patients with pediatric-onset multiple sclerosis (POMS) are often prescribed low-efficacy disease-modifying therapies (DMTs), but a new retrospective analysis suggests that, like adults, this patient population may benefit from early treatment with high-efficacy DMTs.
“I think it’s very important to highlight that we are seeing that traditionally, kids are just started on lower-efficacy treatments and they keep relapsing. If we can show that when they get transitioned to high-efficacy treatments, the relapses are lessening, I’m hoping that can then push for better clinical trials with pediatric patients included,” said Frederick Bassal, DO, who presented the study during a poster session at the 2024 annual meeting of the American Academy of Neurology. He is a pediatric neurologist at University of California, Davis.
The first line for POMS is generally low-efficacy DMTs like interferon-beta and glatiramer acetate, but these medications may not effectively control disease progression, according to the study authors, and this could lead to pediatric patients being changed to more potent therapies. That can include moderate-efficacy drugs like S1P inhibitors and fumarates, or high-efficacy DMTS such as B cell depletors and alpha 4 integrin receptor antibodies.
Treatment Strategies
“Right now what we’re seeing is the conservative approach — starting low and working up with the younger and adolescent patients. I’m speculating, and I want to look more into it. Is [it maybe] because of insurance approval?” said study coauthor Amara Miller, a medical student at the University of Arizona College of Medicine in Phoenix.
The findings aren’t surprising, according to Barbara Giesser, MD, who was asked to comment on the study. “It is in line with what we think we know about people with adult MS — that if you start early on with a more effective therapy, you tend to have better outcomes,” said Dr. Giesser, director of the MS program at the Pacific Neuroscience Institute.
Another reason to consider higher-efficacy DMTs is that children with MS can have cognitive problems and delays. “There’s a suggestion that if you treat with highly-effective DMT that you might be able to abrogate some of that,” said Dr. Giesser.
Among the approximately two dozen FDA-approved disease-modifying therapies for MS, only fingolimod (Gilenya, Novartis) is approved for children and adolescents. “All of the others are used off label, but I think perhaps, if you have more studies that [show] that children do better if you treat with more effective therapies early on, perhaps we might see more on-label indications for use in a pediatric population,” said Dr. Giesser.
The finding that obesity was associated with a higher likelihood of having multiple therapies is also interesting, she said. “We’re beginning to see that obesity in adults as well seems to portend less favorable neurologic outcomes.”
Study Methodology
The researchers analyzed data from 135 POMS patients between 2012 and 2023.
The mean age of participants was 15 years, 60% were female, and 120 of 135 were White, while 76 were of Hispanic ethnicity. Overweight and obesity were common, with 36 and 43 participants in each category. The initial therapy was a low-efficacy DMT in 23.0% of participants, moderate-efficacy in 37.0%, and high-efficacy in 24.4%, while 1.5% received some other kind of medication and 14.1% received no medication. The annualized relapse rate was 0.932, and the mean EDSS score was 0.88.
Patients who underwent three or medication changes had lower EDSS scores than those who underwent zero to 2 (P = .00607).
Over the course of the study, the percentage of patients who received high-efficacy DMTs rose from 25.9% to 48.9%, largely due to changes in medication. Of those initially prescribed low-efficacy DMTs, 77.4% were eventually switched to high-efficacy DMTs.
Every patient who underwent three or more medication changes was initially prescribed a low-efficacy DMT.
Patients started on low-efficacy drugs had a mean of 1.42 medication changes, compared with 0.94 in the moderate-efficacy group and 0.51 in the high-efficacy group. The reasons for changing from the first medication included relapse (36), side effects (11), patient choice or compliance (8), and pregnancy (2).
Patients 10 years or younger were more likely to be initially prescribed a low-efficacy therapy (odds ratio [OR], 5.72; P = .0366), while older patients were more likely to be prescribed moderate- or high-efficacy therapies (OR, 14.44; P = .0012).
There were more total medication changes in the low-efficacy group than the high initial DMT group (P = .000305).
Asked what advice they would give to physicians treating POMS patients, Ms. Miller suggested a top-down approach. “We want to look at if maybe we can start with higher efficacy DMT’s and maybe titering it down. That may be an option,” said Ms. Miller.
Dr. Bassal highlighted the importance of shared decision-making. “We want to go over the options, that we recommend higher-efficacy [DMTs] for these reasons. But every individual is different. And there may be fears that are very reasonable that families have. I think in those cases, it’s also reasonable to make a shared decision. And if that means going with something like an oral, moderate- to lower-efficacy [therapy], that’s okay, because compliance is key, and if you start something where the family is afraid of side effects, or there are side effects, then you kind of lost that opportunity,” he said.
Dr. Bassal, Dr. Giesser, and Ms. Miller have no relevant financial disclosures.
DENVER — Patients with pediatric-onset multiple sclerosis (POMS) are often prescribed low-efficacy disease-modifying therapies (DMTs), but a new retrospective analysis suggests that, like adults, this patient population may benefit from early treatment with high-efficacy DMTs.
“I think it’s very important to highlight that we are seeing that traditionally, kids are just started on lower-efficacy treatments and they keep relapsing. If we can show that when they get transitioned to high-efficacy treatments, the relapses are lessening, I’m hoping that can then push for better clinical trials with pediatric patients included,” said Frederick Bassal, DO, who presented the study during a poster session at the 2024 annual meeting of the American Academy of Neurology. He is a pediatric neurologist at University of California, Davis.
The first line for POMS is generally low-efficacy DMTs like interferon-beta and glatiramer acetate, but these medications may not effectively control disease progression, according to the study authors, and this could lead to pediatric patients being changed to more potent therapies. That can include moderate-efficacy drugs like S1P inhibitors and fumarates, or high-efficacy DMTS such as B cell depletors and alpha 4 integrin receptor antibodies.
Treatment Strategies
“Right now what we’re seeing is the conservative approach — starting low and working up with the younger and adolescent patients. I’m speculating, and I want to look more into it. Is [it maybe] because of insurance approval?” said study coauthor Amara Miller, a medical student at the University of Arizona College of Medicine in Phoenix.
The findings aren’t surprising, according to Barbara Giesser, MD, who was asked to comment on the study. “It is in line with what we think we know about people with adult MS — that if you start early on with a more effective therapy, you tend to have better outcomes,” said Dr. Giesser, director of the MS program at the Pacific Neuroscience Institute.
Another reason to consider higher-efficacy DMTs is that children with MS can have cognitive problems and delays. “There’s a suggestion that if you treat with highly-effective DMT that you might be able to abrogate some of that,” said Dr. Giesser.
Among the approximately two dozen FDA-approved disease-modifying therapies for MS, only fingolimod (Gilenya, Novartis) is approved for children and adolescents. “All of the others are used off label, but I think perhaps, if you have more studies that [show] that children do better if you treat with more effective therapies early on, perhaps we might see more on-label indications for use in a pediatric population,” said Dr. Giesser.
The finding that obesity was associated with a higher likelihood of having multiple therapies is also interesting, she said. “We’re beginning to see that obesity in adults as well seems to portend less favorable neurologic outcomes.”
Study Methodology
The researchers analyzed data from 135 POMS patients between 2012 and 2023.
The mean age of participants was 15 years, 60% were female, and 120 of 135 were White, while 76 were of Hispanic ethnicity. Overweight and obesity were common, with 36 and 43 participants in each category. The initial therapy was a low-efficacy DMT in 23.0% of participants, moderate-efficacy in 37.0%, and high-efficacy in 24.4%, while 1.5% received some other kind of medication and 14.1% received no medication. The annualized relapse rate was 0.932, and the mean EDSS score was 0.88.
Patients who underwent three or medication changes had lower EDSS scores than those who underwent zero to 2 (P = .00607).
Over the course of the study, the percentage of patients who received high-efficacy DMTs rose from 25.9% to 48.9%, largely due to changes in medication. Of those initially prescribed low-efficacy DMTs, 77.4% were eventually switched to high-efficacy DMTs.
Every patient who underwent three or more medication changes was initially prescribed a low-efficacy DMT.
Patients started on low-efficacy drugs had a mean of 1.42 medication changes, compared with 0.94 in the moderate-efficacy group and 0.51 in the high-efficacy group. The reasons for changing from the first medication included relapse (36), side effects (11), patient choice or compliance (8), and pregnancy (2).
Patients 10 years or younger were more likely to be initially prescribed a low-efficacy therapy (odds ratio [OR], 5.72; P = .0366), while older patients were more likely to be prescribed moderate- or high-efficacy therapies (OR, 14.44; P = .0012).
There were more total medication changes in the low-efficacy group than the high initial DMT group (P = .000305).
Asked what advice they would give to physicians treating POMS patients, Ms. Miller suggested a top-down approach. “We want to look at if maybe we can start with higher efficacy DMT’s and maybe titering it down. That may be an option,” said Ms. Miller.
Dr. Bassal highlighted the importance of shared decision-making. “We want to go over the options, that we recommend higher-efficacy [DMTs] for these reasons. But every individual is different. And there may be fears that are very reasonable that families have. I think in those cases, it’s also reasonable to make a shared decision. And if that means going with something like an oral, moderate- to lower-efficacy [therapy], that’s okay, because compliance is key, and if you start something where the family is afraid of side effects, or there are side effects, then you kind of lost that opportunity,” he said.
Dr. Bassal, Dr. Giesser, and Ms. Miller have no relevant financial disclosures.
FROM AAN 2024
Lidocaine Nerve Block Effective for Severe, Refractory Migraine in Children
DENVER — , results of a randomized controlled trial show.
Investigators found children receiving bilateral occipital nerve blocks with 2% lidocaine had significantly greater pain relief than that of peers receiving saline injections.
Cases series have shown a benefit of peripheral nerve blocks (PNBs) — injections of local anesthetics over branches of the occipital or trigeminal nerve — for severe, refractory headache in children.
Although 80% of pediatric headache specialists use PNBs, there is “inconsistent insurance coverage” for this treatment, which had not been tested in a randomized controlled trial in children before now, lead investigator Christina Szperka, MD, with the Pediatric Headache Program, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, told delegates attending the 2024 annual meeting of the American Academy of Neurology.
Significant Results
Investigators enrolled 58 children and adolescents with acute status migrainosus. The mean age was 16 years, and reported gender was female for 44 participants, male for 11 participants, and nonbinary or transgender in 3 participants. Participants had a migraine flare duration of 22 days and had not responded to other treatments.
All participants had topical lidocaine cream applied for 30 minutes as a run-in step and could decline injections if they experienced sufficient benefit from cream alone.
“We used a lidocaine cream lead-in for two reasons. One was to try to see if we could address the issue of high placebo response in pediatric trials in particular, and also to see if we could help with blinding to injection,” said Dr. Szperka.
Topical lidocaine cream led to a small decrease in pain score overall (0.2 point on a 0-10 scale), and all participants proceeded to randomized blinded bilateral greater occipital nerve injection with 2% lidocaine or saline, she reported.
On the primary endpoint — change in pain score at 30 minutes — lidocaine was significantly more effective than saline, achieving a 2.3-point decrease on average (on a 0-10 scale) vs a 1.1-point decrease with saline (P = .01).
A 2-point pain reduction was achieved in 69% of patients in the lidocaine group versus 34% in the saline group.
Three quarters (76%) of patients getting lidocaine reported at least partial relief in severity or location of pain compared with 48% of those getting saline (P = .03). Rates of pain freedom at 30 minutes were 17% and 7%, respectively, and at 24 hours were 14% and 0%, respectively.
The majority of adverse events were mild and fairly equal across groups and included anxiety, worsening headache, injection site pain, dizziness, and numbness (more so with lidocaine). There was one case of anaphylaxis after lidocaine injection.
Quite unexpectedly, said Dr. Szperka, patients rated the saline injection as more painful than the lidocaine injection. “This was not what I expected going in, and I think is relevant for future trials,” she said.
Encouraging Results
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, said that as a neurologist and pain physician, he sees firsthand the “devastating impact of status migrainosus on children.”
“These debilitating headaches can rob them of precious school days, hindering learning and social interaction,” said Dr. Lakhan. “The constant pain and fear of the next attack can also take a toll on their emotional well-being.”
The impact on families is significant as well, highlighting the need to find more effective treatments, Dr. Lakhan said.
“Traditionally, we’ve relied on case studies to see the benefits of nerve blocks for migraine in younger patients. This is the first randomized controlled trial that shows lidocaine injections can be significantly more effective than a placebo for these unrelenting migraines,” he said.
“It’s important to note that this is a relatively small study, and not without safety concerns, including rare but potentially life-threatening anaphylaxis to lidocaine,” Dr. Lakhan added. “More research is needed, but these findings are encouraging. Lidocaine injections could become a valuable tool for managing treatment-resistant migraines in adolescents and young adults.”
The study was supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Szperka is a consultant for AbbVie and Teva; serves on a Data Safety Monitoring Board for Eli Lilly and Upsher-Smith; and is a site principal investigator for AbbVie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Lakhan had no disclosures.
A version of this article appeared on Medscape.com.
DENVER — , results of a randomized controlled trial show.
Investigators found children receiving bilateral occipital nerve blocks with 2% lidocaine had significantly greater pain relief than that of peers receiving saline injections.
Cases series have shown a benefit of peripheral nerve blocks (PNBs) — injections of local anesthetics over branches of the occipital or trigeminal nerve — for severe, refractory headache in children.
Although 80% of pediatric headache specialists use PNBs, there is “inconsistent insurance coverage” for this treatment, which had not been tested in a randomized controlled trial in children before now, lead investigator Christina Szperka, MD, with the Pediatric Headache Program, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, told delegates attending the 2024 annual meeting of the American Academy of Neurology.
Significant Results
Investigators enrolled 58 children and adolescents with acute status migrainosus. The mean age was 16 years, and reported gender was female for 44 participants, male for 11 participants, and nonbinary or transgender in 3 participants. Participants had a migraine flare duration of 22 days and had not responded to other treatments.
All participants had topical lidocaine cream applied for 30 minutes as a run-in step and could decline injections if they experienced sufficient benefit from cream alone.
“We used a lidocaine cream lead-in for two reasons. One was to try to see if we could address the issue of high placebo response in pediatric trials in particular, and also to see if we could help with blinding to injection,” said Dr. Szperka.
Topical lidocaine cream led to a small decrease in pain score overall (0.2 point on a 0-10 scale), and all participants proceeded to randomized blinded bilateral greater occipital nerve injection with 2% lidocaine or saline, she reported.
On the primary endpoint — change in pain score at 30 minutes — lidocaine was significantly more effective than saline, achieving a 2.3-point decrease on average (on a 0-10 scale) vs a 1.1-point decrease with saline (P = .01).
A 2-point pain reduction was achieved in 69% of patients in the lidocaine group versus 34% in the saline group.
Three quarters (76%) of patients getting lidocaine reported at least partial relief in severity or location of pain compared with 48% of those getting saline (P = .03). Rates of pain freedom at 30 minutes were 17% and 7%, respectively, and at 24 hours were 14% and 0%, respectively.
The majority of adverse events were mild and fairly equal across groups and included anxiety, worsening headache, injection site pain, dizziness, and numbness (more so with lidocaine). There was one case of anaphylaxis after lidocaine injection.
Quite unexpectedly, said Dr. Szperka, patients rated the saline injection as more painful than the lidocaine injection. “This was not what I expected going in, and I think is relevant for future trials,” she said.
Encouraging Results
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, said that as a neurologist and pain physician, he sees firsthand the “devastating impact of status migrainosus on children.”
“These debilitating headaches can rob them of precious school days, hindering learning and social interaction,” said Dr. Lakhan. “The constant pain and fear of the next attack can also take a toll on their emotional well-being.”
The impact on families is significant as well, highlighting the need to find more effective treatments, Dr. Lakhan said.
“Traditionally, we’ve relied on case studies to see the benefits of nerve blocks for migraine in younger patients. This is the first randomized controlled trial that shows lidocaine injections can be significantly more effective than a placebo for these unrelenting migraines,” he said.
“It’s important to note that this is a relatively small study, and not without safety concerns, including rare but potentially life-threatening anaphylaxis to lidocaine,” Dr. Lakhan added. “More research is needed, but these findings are encouraging. Lidocaine injections could become a valuable tool for managing treatment-resistant migraines in adolescents and young adults.”
The study was supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Szperka is a consultant for AbbVie and Teva; serves on a Data Safety Monitoring Board for Eli Lilly and Upsher-Smith; and is a site principal investigator for AbbVie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Lakhan had no disclosures.
A version of this article appeared on Medscape.com.
DENVER — , results of a randomized controlled trial show.
Investigators found children receiving bilateral occipital nerve blocks with 2% lidocaine had significantly greater pain relief than that of peers receiving saline injections.
Cases series have shown a benefit of peripheral nerve blocks (PNBs) — injections of local anesthetics over branches of the occipital or trigeminal nerve — for severe, refractory headache in children.
Although 80% of pediatric headache specialists use PNBs, there is “inconsistent insurance coverage” for this treatment, which had not been tested in a randomized controlled trial in children before now, lead investigator Christina Szperka, MD, with the Pediatric Headache Program, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, told delegates attending the 2024 annual meeting of the American Academy of Neurology.
Significant Results
Investigators enrolled 58 children and adolescents with acute status migrainosus. The mean age was 16 years, and reported gender was female for 44 participants, male for 11 participants, and nonbinary or transgender in 3 participants. Participants had a migraine flare duration of 22 days and had not responded to other treatments.
All participants had topical lidocaine cream applied for 30 minutes as a run-in step and could decline injections if they experienced sufficient benefit from cream alone.
“We used a lidocaine cream lead-in for two reasons. One was to try to see if we could address the issue of high placebo response in pediatric trials in particular, and also to see if we could help with blinding to injection,” said Dr. Szperka.
Topical lidocaine cream led to a small decrease in pain score overall (0.2 point on a 0-10 scale), and all participants proceeded to randomized blinded bilateral greater occipital nerve injection with 2% lidocaine or saline, she reported.
On the primary endpoint — change in pain score at 30 minutes — lidocaine was significantly more effective than saline, achieving a 2.3-point decrease on average (on a 0-10 scale) vs a 1.1-point decrease with saline (P = .01).
A 2-point pain reduction was achieved in 69% of patients in the lidocaine group versus 34% in the saline group.
Three quarters (76%) of patients getting lidocaine reported at least partial relief in severity or location of pain compared with 48% of those getting saline (P = .03). Rates of pain freedom at 30 minutes were 17% and 7%, respectively, and at 24 hours were 14% and 0%, respectively.
The majority of adverse events were mild and fairly equal across groups and included anxiety, worsening headache, injection site pain, dizziness, and numbness (more so with lidocaine). There was one case of anaphylaxis after lidocaine injection.
Quite unexpectedly, said Dr. Szperka, patients rated the saline injection as more painful than the lidocaine injection. “This was not what I expected going in, and I think is relevant for future trials,” she said.
Encouraging Results
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, said that as a neurologist and pain physician, he sees firsthand the “devastating impact of status migrainosus on children.”
“These debilitating headaches can rob them of precious school days, hindering learning and social interaction,” said Dr. Lakhan. “The constant pain and fear of the next attack can also take a toll on their emotional well-being.”
The impact on families is significant as well, highlighting the need to find more effective treatments, Dr. Lakhan said.
“Traditionally, we’ve relied on case studies to see the benefits of nerve blocks for migraine in younger patients. This is the first randomized controlled trial that shows lidocaine injections can be significantly more effective than a placebo for these unrelenting migraines,” he said.
“It’s important to note that this is a relatively small study, and not without safety concerns, including rare but potentially life-threatening anaphylaxis to lidocaine,” Dr. Lakhan added. “More research is needed, but these findings are encouraging. Lidocaine injections could become a valuable tool for managing treatment-resistant migraines in adolescents and young adults.”
The study was supported by a grant from the National Institute of Neurological Disorders and Stroke. Dr. Szperka is a consultant for AbbVie and Teva; serves on a Data Safety Monitoring Board for Eli Lilly and Upsher-Smith; and is a site principal investigator for AbbVie, Amgen, Biohaven/Pfizer, Teva, and Theranica. Dr. Lakhan had no disclosures.
A version of this article appeared on Medscape.com.
FROM AAN 2024
New and Improved Option for Detecting Neurologic Pathogens?
DENVER — , results of a real-world analysis show.
Metagenomic next-generation sequencing (mNGS) of RNA and DNA from cerebrospinal fluid (CSF) simultaneously tests for a wide range of infectious agents and identifies individual pathogens, including viruses, bacteria, fungi, and parasites. About half of patients with a suspected central nervous system (CNS) infection may go undiagnosed due to a lack of tools that detect rare pathogens. Although mNGS is currently available only in specialized laboratories, expanding access to the diagnostic could address this problem, investigators noted.
“Our results justify incorporation of CSF mNGS testing as part of the routine diagnostic workup in hospitalized patients who present with potential central nervous system infections,” study investigator Charles Chiu, MD, PhD, professor in the Department of Laboratory Medicine as well as Medicine and Department of Medicine – Infectious Diseases and director of the Clinical Microbiology Laboratory, University of California San Fransisco (UCSF), said at a press conference.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
‘Real-World’ Performance
Accurate diagnosis of CNS infections on the basis of CSF, imaging, patient history, and presentation is challenging, the researchers noted. “Roughly 50% of patients who present with a presumed central nervous system infection actually end up without a diagnosis,” Dr. Chiu said.
This is due to the lack of diagnostic tests for rare pathogens and because noninfectious conditions like cancer, autoantibody syndrome, or vasculitis can mimic an infection, he added.
CSF is “very limiting,” Dr. Chiu noted. “We are unable, practically, from a volume perspective, as well as a cost and turnaround time perspective, to be able to send off every possible test for every possible organism.”
The inability to rapidly pinpoint the cause of an infectious disease like meningitis or encephalitis can cause delays in appropriate treatment.
To assess the “real-world” performance of mNGS, researchers collected 4828 samples from mainly hospitalized patients across the United States and elsewhere from 2016 to 2023.
Overall, the test detected at least one pathogen in 16.6% of cases. More than 70% were DNA or RNA viruses, followed by bacteria, fungi, and parasites.
High Sensitivity
The technology was also able to detect novel or emerging neurotropic pathogens, including a yellow fever virus responsible for a transfusion-transmitted encephalitis outbreak and Fusarium solani, which caused a fungal meningitis outbreak.
Investigators also conducted a chart review on a subset of 1052 patients at UCSF to compare the performance of CSF nMGS testing with commonly used in-hospital diagnostic tests.
“We showed that as a single test, spinal fluid mNGS has an overall sensitivity of 63%, specificity of 99%, and accuracy of 90%,” said Dr. Chiu.
The sensitivity of mNGS was significantly higher compared with direct-detection testing from CSF (46%); direct-detection testing performed on samples other than CSF, such as blood (15%); and indirect serologic testing looking for antibodies (29%) (P < .001 for all).
This suggests that mNGS could potentially “detect the hundreds of different pathogens that cause clinically indistinguishable infections,” Dr. Chui said.
mNGS testing is currently confined to large specialized or reference laboratories. For greater access to the test, routine clinical labs or hospital labs would have to implement it, said Dr. Chiu.
“If you can bring the technology to the point of care, directly to the hospital lab that’s running the test, we can produce results that would have a more rapid impact on patients,” he said.
Guiding Therapy
Ultimately, he added, the purpose of a diagnostic test is to “generate actionable information that could potentially guide therapy.”
Researchers are now evaluating medical charts of the same subcohort of patients to determine whether the test made a clinical difference.
“We want to know if it had a positive or negative or no clinical impact on the management and treatment of patients,” said Dr. Chiu. “Producing data like this will help us define the role of this test in the future as part of the diagnostic paradigm.”
The researchers are also working on a cost/benefit analysis, and Dr. Chiu said that US Food and Drug Administration approval of the test is needed “to establish a blueprint for reimbursement.”
Commenting on the findings, Jessica Robinson-Papp, MD, professor and vice chair of clinical research, Department of Neurology, Icahn School of Medicine, New York, said that the technology could be useful, especially in developing countries with higher rates of CNS infections.
“What’s really exciting about it is you can take a very small CSF sample, like 1 mL, and in an unbiased way just screen for all different kinds of pathogens including both DNA and RNA viruses, parasites, bacteria, and fungi, and sort of come up with whether there’s a pathogen there or whether there is no pathogen there,” she said.
However, there’s a chance that this sensitive technique will pick up contaminants, she added. “For example, if there’s a little environmental bacterium either on the skin or in the water used for processing, it can get reads on that.”
The study received support from Delve Bio and the Chan-Zuckerberg Biohub.
Dr. Chiu has received personal compensation for serving on a Scientific Advisory or Data Safety Monitoring Board for Biomeme and has stock in Delve Bio, Poppy Health, Mammoth Biosciences, and BiomeSense and has received intellectual property interests from a discovery or technology relating to healthcare. Dr. Robinson-Papp has no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
DENVER — , results of a real-world analysis show.
Metagenomic next-generation sequencing (mNGS) of RNA and DNA from cerebrospinal fluid (CSF) simultaneously tests for a wide range of infectious agents and identifies individual pathogens, including viruses, bacteria, fungi, and parasites. About half of patients with a suspected central nervous system (CNS) infection may go undiagnosed due to a lack of tools that detect rare pathogens. Although mNGS is currently available only in specialized laboratories, expanding access to the diagnostic could address this problem, investigators noted.
“Our results justify incorporation of CSF mNGS testing as part of the routine diagnostic workup in hospitalized patients who present with potential central nervous system infections,” study investigator Charles Chiu, MD, PhD, professor in the Department of Laboratory Medicine as well as Medicine and Department of Medicine – Infectious Diseases and director of the Clinical Microbiology Laboratory, University of California San Fransisco (UCSF), said at a press conference.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
‘Real-World’ Performance
Accurate diagnosis of CNS infections on the basis of CSF, imaging, patient history, and presentation is challenging, the researchers noted. “Roughly 50% of patients who present with a presumed central nervous system infection actually end up without a diagnosis,” Dr. Chiu said.
This is due to the lack of diagnostic tests for rare pathogens and because noninfectious conditions like cancer, autoantibody syndrome, or vasculitis can mimic an infection, he added.
CSF is “very limiting,” Dr. Chiu noted. “We are unable, practically, from a volume perspective, as well as a cost and turnaround time perspective, to be able to send off every possible test for every possible organism.”
The inability to rapidly pinpoint the cause of an infectious disease like meningitis or encephalitis can cause delays in appropriate treatment.
To assess the “real-world” performance of mNGS, researchers collected 4828 samples from mainly hospitalized patients across the United States and elsewhere from 2016 to 2023.
Overall, the test detected at least one pathogen in 16.6% of cases. More than 70% were DNA or RNA viruses, followed by bacteria, fungi, and parasites.
High Sensitivity
The technology was also able to detect novel or emerging neurotropic pathogens, including a yellow fever virus responsible for a transfusion-transmitted encephalitis outbreak and Fusarium solani, which caused a fungal meningitis outbreak.
Investigators also conducted a chart review on a subset of 1052 patients at UCSF to compare the performance of CSF nMGS testing with commonly used in-hospital diagnostic tests.
“We showed that as a single test, spinal fluid mNGS has an overall sensitivity of 63%, specificity of 99%, and accuracy of 90%,” said Dr. Chiu.
The sensitivity of mNGS was significantly higher compared with direct-detection testing from CSF (46%); direct-detection testing performed on samples other than CSF, such as blood (15%); and indirect serologic testing looking for antibodies (29%) (P < .001 for all).
This suggests that mNGS could potentially “detect the hundreds of different pathogens that cause clinically indistinguishable infections,” Dr. Chui said.
mNGS testing is currently confined to large specialized or reference laboratories. For greater access to the test, routine clinical labs or hospital labs would have to implement it, said Dr. Chiu.
“If you can bring the technology to the point of care, directly to the hospital lab that’s running the test, we can produce results that would have a more rapid impact on patients,” he said.
Guiding Therapy
Ultimately, he added, the purpose of a diagnostic test is to “generate actionable information that could potentially guide therapy.”
Researchers are now evaluating medical charts of the same subcohort of patients to determine whether the test made a clinical difference.
“We want to know if it had a positive or negative or no clinical impact on the management and treatment of patients,” said Dr. Chiu. “Producing data like this will help us define the role of this test in the future as part of the diagnostic paradigm.”
The researchers are also working on a cost/benefit analysis, and Dr. Chiu said that US Food and Drug Administration approval of the test is needed “to establish a blueprint for reimbursement.”
Commenting on the findings, Jessica Robinson-Papp, MD, professor and vice chair of clinical research, Department of Neurology, Icahn School of Medicine, New York, said that the technology could be useful, especially in developing countries with higher rates of CNS infections.
“What’s really exciting about it is you can take a very small CSF sample, like 1 mL, and in an unbiased way just screen for all different kinds of pathogens including both DNA and RNA viruses, parasites, bacteria, and fungi, and sort of come up with whether there’s a pathogen there or whether there is no pathogen there,” she said.
However, there’s a chance that this sensitive technique will pick up contaminants, she added. “For example, if there’s a little environmental bacterium either on the skin or in the water used for processing, it can get reads on that.”
The study received support from Delve Bio and the Chan-Zuckerberg Biohub.
Dr. Chiu has received personal compensation for serving on a Scientific Advisory or Data Safety Monitoring Board for Biomeme and has stock in Delve Bio, Poppy Health, Mammoth Biosciences, and BiomeSense and has received intellectual property interests from a discovery or technology relating to healthcare. Dr. Robinson-Papp has no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
DENVER — , results of a real-world analysis show.
Metagenomic next-generation sequencing (mNGS) of RNA and DNA from cerebrospinal fluid (CSF) simultaneously tests for a wide range of infectious agents and identifies individual pathogens, including viruses, bacteria, fungi, and parasites. About half of patients with a suspected central nervous system (CNS) infection may go undiagnosed due to a lack of tools that detect rare pathogens. Although mNGS is currently available only in specialized laboratories, expanding access to the diagnostic could address this problem, investigators noted.
“Our results justify incorporation of CSF mNGS testing as part of the routine diagnostic workup in hospitalized patients who present with potential central nervous system infections,” study investigator Charles Chiu, MD, PhD, professor in the Department of Laboratory Medicine as well as Medicine and Department of Medicine – Infectious Diseases and director of the Clinical Microbiology Laboratory, University of California San Fransisco (UCSF), said at a press conference.
The findings were presented at the 2024 annual meeting of the American Academy of Neurology (AAN).
‘Real-World’ Performance
Accurate diagnosis of CNS infections on the basis of CSF, imaging, patient history, and presentation is challenging, the researchers noted. “Roughly 50% of patients who present with a presumed central nervous system infection actually end up without a diagnosis,” Dr. Chiu said.
This is due to the lack of diagnostic tests for rare pathogens and because noninfectious conditions like cancer, autoantibody syndrome, or vasculitis can mimic an infection, he added.
CSF is “very limiting,” Dr. Chiu noted. “We are unable, practically, from a volume perspective, as well as a cost and turnaround time perspective, to be able to send off every possible test for every possible organism.”
The inability to rapidly pinpoint the cause of an infectious disease like meningitis or encephalitis can cause delays in appropriate treatment.
To assess the “real-world” performance of mNGS, researchers collected 4828 samples from mainly hospitalized patients across the United States and elsewhere from 2016 to 2023.
Overall, the test detected at least one pathogen in 16.6% of cases. More than 70% were DNA or RNA viruses, followed by bacteria, fungi, and parasites.
High Sensitivity
The technology was also able to detect novel or emerging neurotropic pathogens, including a yellow fever virus responsible for a transfusion-transmitted encephalitis outbreak and Fusarium solani, which caused a fungal meningitis outbreak.
Investigators also conducted a chart review on a subset of 1052 patients at UCSF to compare the performance of CSF nMGS testing with commonly used in-hospital diagnostic tests.
“We showed that as a single test, spinal fluid mNGS has an overall sensitivity of 63%, specificity of 99%, and accuracy of 90%,” said Dr. Chiu.
The sensitivity of mNGS was significantly higher compared with direct-detection testing from CSF (46%); direct-detection testing performed on samples other than CSF, such as blood (15%); and indirect serologic testing looking for antibodies (29%) (P < .001 for all).
This suggests that mNGS could potentially “detect the hundreds of different pathogens that cause clinically indistinguishable infections,” Dr. Chui said.
mNGS testing is currently confined to large specialized or reference laboratories. For greater access to the test, routine clinical labs or hospital labs would have to implement it, said Dr. Chiu.
“If you can bring the technology to the point of care, directly to the hospital lab that’s running the test, we can produce results that would have a more rapid impact on patients,” he said.
Guiding Therapy
Ultimately, he added, the purpose of a diagnostic test is to “generate actionable information that could potentially guide therapy.”
Researchers are now evaluating medical charts of the same subcohort of patients to determine whether the test made a clinical difference.
“We want to know if it had a positive or negative or no clinical impact on the management and treatment of patients,” said Dr. Chiu. “Producing data like this will help us define the role of this test in the future as part of the diagnostic paradigm.”
The researchers are also working on a cost/benefit analysis, and Dr. Chiu said that US Food and Drug Administration approval of the test is needed “to establish a blueprint for reimbursement.”
Commenting on the findings, Jessica Robinson-Papp, MD, professor and vice chair of clinical research, Department of Neurology, Icahn School of Medicine, New York, said that the technology could be useful, especially in developing countries with higher rates of CNS infections.
“What’s really exciting about it is you can take a very small CSF sample, like 1 mL, and in an unbiased way just screen for all different kinds of pathogens including both DNA and RNA viruses, parasites, bacteria, and fungi, and sort of come up with whether there’s a pathogen there or whether there is no pathogen there,” she said.
However, there’s a chance that this sensitive technique will pick up contaminants, she added. “For example, if there’s a little environmental bacterium either on the skin or in the water used for processing, it can get reads on that.”
The study received support from Delve Bio and the Chan-Zuckerberg Biohub.
Dr. Chiu has received personal compensation for serving on a Scientific Advisory or Data Safety Monitoring Board for Biomeme and has stock in Delve Bio, Poppy Health, Mammoth Biosciences, and BiomeSense and has received intellectual property interests from a discovery or technology relating to healthcare. Dr. Robinson-Papp has no relevant conflicts of interest.
A version of this article appeared on Medscape.com.
FROM AAN 2024
Vaporized Cannabis for Acute Migraine Yields Rapid, Sustained Relief
DENVER — , new research suggests.
“In this single-center randomized controlled trial across 247 treated migraine attacks, four puffs of vaporized THC-CBD mix were efficacious for acute migraine treatment,” said study investigator Nathaniel Marc Schuster, MD, with University of California San Diego Center for Pain Medicine.
The superiority of THC-CBD over placebo was “unlikely explained by unmasking given that in our blinding analysis most patients who got THC actually did not think they got some THC,” Dr. Schuster said.
He presented the results at the 2024 annual meeting of the American Academy of Neurology.
Sustained Pain Relief
Preclinical and retrospective studies point to antimigraine effects of cannabinoids, yet strong evidence of efficacy from a randomized controlled trial has been lacking.
The researchers tested the efficacy of cannabis for acute migraine in what they report is the first randomized, double-blind, placebo-controlled, crossover trial of adults with migraine.
Participants treated up to four separate moderate to severe migraine attacks, each with one of four different treatments. The four treatments were: 6% THC, 11% CBD, a mix of 6% THC and 11% CBD, or placebo flower from the National Institute on Drug Abuse that has a similar taste and smell to the other products.
The four treatments were vaporized in a randomized order, with at least 1 week washout between treatments. The primary endpoint was pain relief at 2 hours from vaporization. Secondary endpoints were freedom from pain and most bothersome symptom (MBS) at 2 hours from vaporization.
Of the 92 enrolled patients (mean age 41 years, 83% women), 19 treated zero migraine attacks thus leaving 73 patients who treated a total of 247 migraine attacks over the 1-year study.
The THC-CBD mix was superior to placebo at achieving pain relief (67.2% vs 46.6%; P = .016), pain freedom (34.5% vs 15.5%; P = .017), and MBS freedom (60.3% vs 34.5%; P = .005) at 2 hours.
The THC-CBD mix was also superior to placebo for sustained pain freedom at 24 hours and sustained MBS freedom at 24 and 48 hours.
There were no serious adverse events. The THC-CBD mix was better tolerated than THC-only was, with lower rates of euphoria and cognitive impairment and lower subjective highness, Dr. Schuster said.
Adverse events were more common with THC only (vs THC-CBD) “and this is really expected because CBD is known to bring down the side effects of THC,” Dr. Schuster noted.
Summing up his presentation, Dr. Schuster said, “This is one single-center study, and, of course, we need more data. We need to study the rates of medication overuse headache and the rates of cannabis use disorder that may develop with the use of cannabis for migraine.”
Cautious Optimism
Reached for comment, Hsiangkuo (Scott) Yuan, MD, PhD, Department of Neurology, Thomas Jefferson University, and director of clinical research, Jefferson Headache Center, Philadelphia, Pennsylvania, noted that the “statistically significant” differences between THC-CBD versus placebo on 2-hour pain relief, pain freedom and MBS freedom are “certainly very exciting, especially when no serious adverse event was reported.”
“Since THC has a narrow therapeutic window for analgesia (too high causes psychoactive side effects and may even worsen the pain), its dosing needs to be carefully controlled. The study was wisely designed to ensure uniform dosing from the vaporizer, which is usually safer than smoking or a vape pen and has a quicker onset than ingestion for acute usage,” said Dr. Yuan, who was not involved in the study.
“However, the optimal THC-CBD ratio and potency (percent THC) for acute migraine remain to be studied. Perhaps there is an individualized dose that can be obtained by titration. We also don’t know if the effect changes after repeated use,” Dr. Yuan cautioned.
He also noted that cannabis use was associated with medication overuse headache in a retrospective study, “although the causality remains to be determined.”
“While there was no serious adverse event, it is not completely risk-free, especially when cannabis is used repeatedly for a short duration. Since the physician does not have direct control over what happens at the dispensary, we need to counsel our patients more carefully when recommending cannabis/cannabinoids,” Dr. Yuan said.
Overall, he said he is “cautiously optimistic about cannabis use for acute migraine.”
This was an investigator-initiated study, with no commercial funding. Dr. Schuster has disclosed relationships with Schedule 1 Therapeutics, Averitas, Lundbeck, Eli Lilly, ShiraTronics, and Syneos. In the past 24 months, Dr. Yuan has served as a site investigator for Teva, AbbVie, Ipsen, Parema; received advisory/consultant fees from Salvia, Pfizer, AbbVie, Cerenovus; and royalties from Cambridge University Press and MedLink.
A version of this article appeared on Medscape.com.
DENVER — , new research suggests.
“In this single-center randomized controlled trial across 247 treated migraine attacks, four puffs of vaporized THC-CBD mix were efficacious for acute migraine treatment,” said study investigator Nathaniel Marc Schuster, MD, with University of California San Diego Center for Pain Medicine.
The superiority of THC-CBD over placebo was “unlikely explained by unmasking given that in our blinding analysis most patients who got THC actually did not think they got some THC,” Dr. Schuster said.
He presented the results at the 2024 annual meeting of the American Academy of Neurology.
Sustained Pain Relief
Preclinical and retrospective studies point to antimigraine effects of cannabinoids, yet strong evidence of efficacy from a randomized controlled trial has been lacking.
The researchers tested the efficacy of cannabis for acute migraine in what they report is the first randomized, double-blind, placebo-controlled, crossover trial of adults with migraine.
Participants treated up to four separate moderate to severe migraine attacks, each with one of four different treatments. The four treatments were: 6% THC, 11% CBD, a mix of 6% THC and 11% CBD, or placebo flower from the National Institute on Drug Abuse that has a similar taste and smell to the other products.
The four treatments were vaporized in a randomized order, with at least 1 week washout between treatments. The primary endpoint was pain relief at 2 hours from vaporization. Secondary endpoints were freedom from pain and most bothersome symptom (MBS) at 2 hours from vaporization.
Of the 92 enrolled patients (mean age 41 years, 83% women), 19 treated zero migraine attacks thus leaving 73 patients who treated a total of 247 migraine attacks over the 1-year study.
The THC-CBD mix was superior to placebo at achieving pain relief (67.2% vs 46.6%; P = .016), pain freedom (34.5% vs 15.5%; P = .017), and MBS freedom (60.3% vs 34.5%; P = .005) at 2 hours.
The THC-CBD mix was also superior to placebo for sustained pain freedom at 24 hours and sustained MBS freedom at 24 and 48 hours.
There were no serious adverse events. The THC-CBD mix was better tolerated than THC-only was, with lower rates of euphoria and cognitive impairment and lower subjective highness, Dr. Schuster said.
Adverse events were more common with THC only (vs THC-CBD) “and this is really expected because CBD is known to bring down the side effects of THC,” Dr. Schuster noted.
Summing up his presentation, Dr. Schuster said, “This is one single-center study, and, of course, we need more data. We need to study the rates of medication overuse headache and the rates of cannabis use disorder that may develop with the use of cannabis for migraine.”
Cautious Optimism
Reached for comment, Hsiangkuo (Scott) Yuan, MD, PhD, Department of Neurology, Thomas Jefferson University, and director of clinical research, Jefferson Headache Center, Philadelphia, Pennsylvania, noted that the “statistically significant” differences between THC-CBD versus placebo on 2-hour pain relief, pain freedom and MBS freedom are “certainly very exciting, especially when no serious adverse event was reported.”
“Since THC has a narrow therapeutic window for analgesia (too high causes psychoactive side effects and may even worsen the pain), its dosing needs to be carefully controlled. The study was wisely designed to ensure uniform dosing from the vaporizer, which is usually safer than smoking or a vape pen and has a quicker onset than ingestion for acute usage,” said Dr. Yuan, who was not involved in the study.
“However, the optimal THC-CBD ratio and potency (percent THC) for acute migraine remain to be studied. Perhaps there is an individualized dose that can be obtained by titration. We also don’t know if the effect changes after repeated use,” Dr. Yuan cautioned.
He also noted that cannabis use was associated with medication overuse headache in a retrospective study, “although the causality remains to be determined.”
“While there was no serious adverse event, it is not completely risk-free, especially when cannabis is used repeatedly for a short duration. Since the physician does not have direct control over what happens at the dispensary, we need to counsel our patients more carefully when recommending cannabis/cannabinoids,” Dr. Yuan said.
Overall, he said he is “cautiously optimistic about cannabis use for acute migraine.”
This was an investigator-initiated study, with no commercial funding. Dr. Schuster has disclosed relationships with Schedule 1 Therapeutics, Averitas, Lundbeck, Eli Lilly, ShiraTronics, and Syneos. In the past 24 months, Dr. Yuan has served as a site investigator for Teva, AbbVie, Ipsen, Parema; received advisory/consultant fees from Salvia, Pfizer, AbbVie, Cerenovus; and royalties from Cambridge University Press and MedLink.
A version of this article appeared on Medscape.com.
DENVER — , new research suggests.
“In this single-center randomized controlled trial across 247 treated migraine attacks, four puffs of vaporized THC-CBD mix were efficacious for acute migraine treatment,” said study investigator Nathaniel Marc Schuster, MD, with University of California San Diego Center for Pain Medicine.
The superiority of THC-CBD over placebo was “unlikely explained by unmasking given that in our blinding analysis most patients who got THC actually did not think they got some THC,” Dr. Schuster said.
He presented the results at the 2024 annual meeting of the American Academy of Neurology.
Sustained Pain Relief
Preclinical and retrospective studies point to antimigraine effects of cannabinoids, yet strong evidence of efficacy from a randomized controlled trial has been lacking.
The researchers tested the efficacy of cannabis for acute migraine in what they report is the first randomized, double-blind, placebo-controlled, crossover trial of adults with migraine.
Participants treated up to four separate moderate to severe migraine attacks, each with one of four different treatments. The four treatments were: 6% THC, 11% CBD, a mix of 6% THC and 11% CBD, or placebo flower from the National Institute on Drug Abuse that has a similar taste and smell to the other products.
The four treatments were vaporized in a randomized order, with at least 1 week washout between treatments. The primary endpoint was pain relief at 2 hours from vaporization. Secondary endpoints were freedom from pain and most bothersome symptom (MBS) at 2 hours from vaporization.
Of the 92 enrolled patients (mean age 41 years, 83% women), 19 treated zero migraine attacks thus leaving 73 patients who treated a total of 247 migraine attacks over the 1-year study.
The THC-CBD mix was superior to placebo at achieving pain relief (67.2% vs 46.6%; P = .016), pain freedom (34.5% vs 15.5%; P = .017), and MBS freedom (60.3% vs 34.5%; P = .005) at 2 hours.
The THC-CBD mix was also superior to placebo for sustained pain freedom at 24 hours and sustained MBS freedom at 24 and 48 hours.
There were no serious adverse events. The THC-CBD mix was better tolerated than THC-only was, with lower rates of euphoria and cognitive impairment and lower subjective highness, Dr. Schuster said.
Adverse events were more common with THC only (vs THC-CBD) “and this is really expected because CBD is known to bring down the side effects of THC,” Dr. Schuster noted.
Summing up his presentation, Dr. Schuster said, “This is one single-center study, and, of course, we need more data. We need to study the rates of medication overuse headache and the rates of cannabis use disorder that may develop with the use of cannabis for migraine.”
Cautious Optimism
Reached for comment, Hsiangkuo (Scott) Yuan, MD, PhD, Department of Neurology, Thomas Jefferson University, and director of clinical research, Jefferson Headache Center, Philadelphia, Pennsylvania, noted that the “statistically significant” differences between THC-CBD versus placebo on 2-hour pain relief, pain freedom and MBS freedom are “certainly very exciting, especially when no serious adverse event was reported.”
“Since THC has a narrow therapeutic window for analgesia (too high causes psychoactive side effects and may even worsen the pain), its dosing needs to be carefully controlled. The study was wisely designed to ensure uniform dosing from the vaporizer, which is usually safer than smoking or a vape pen and has a quicker onset than ingestion for acute usage,” said Dr. Yuan, who was not involved in the study.
“However, the optimal THC-CBD ratio and potency (percent THC) for acute migraine remain to be studied. Perhaps there is an individualized dose that can be obtained by titration. We also don’t know if the effect changes after repeated use,” Dr. Yuan cautioned.
He also noted that cannabis use was associated with medication overuse headache in a retrospective study, “although the causality remains to be determined.”
“While there was no serious adverse event, it is not completely risk-free, especially when cannabis is used repeatedly for a short duration. Since the physician does not have direct control over what happens at the dispensary, we need to counsel our patients more carefully when recommending cannabis/cannabinoids,” Dr. Yuan said.
Overall, he said he is “cautiously optimistic about cannabis use for acute migraine.”
This was an investigator-initiated study, with no commercial funding. Dr. Schuster has disclosed relationships with Schedule 1 Therapeutics, Averitas, Lundbeck, Eli Lilly, ShiraTronics, and Syneos. In the past 24 months, Dr. Yuan has served as a site investigator for Teva, AbbVie, Ipsen, Parema; received advisory/consultant fees from Salvia, Pfizer, AbbVie, Cerenovus; and royalties from Cambridge University Press and MedLink.
A version of this article appeared on Medscape.com.
FROM AAN 2024
IV Ketamine Promising for Severe Refractory Headache in Children
DENVER — , new research suggests. In a retrospective chart review, IV ketamine led to in a 50% reduction in pain at discharge, with “nearly two-thirds” of patients having no recurrence within 30 days, noted lead investigator Scott Rosenthal, MD, from the University of Colorado Anschutz Medical Campus, Aurora.
Dr. Rosenthal reported the findings at the 2024 annual meeting of the American Academy of Neurology.
Statistically Significant Pain Relief
“IV ketamine has shown benefit in nonheadache chronic pain syndromes and refractory mood disorders. Patients with refractory status migraines are often left with ongoing pain and dysfunction after failing typical interventions,” Dr. Rosenthal said.
“Ketamine has emerged as a potential treatment option in this population. However, there’s very little research on the efficacy and tolerability of it in general as well as the pediatric population,” he noted.
Dr. Rosenthal and colleagues took a look back at patients admitted to Children’s Hospital Colorado between 2019 and 2022 for treatment of severe refractory headache who were treated with continuous IV ketamine.
They analyzed 68 encounters of 41 unique patients aged 5-21 years (median age 16 years; 85% girls). Chronic migraine without aura made up 79% of cases.
On presentation, most patients had an exacerbation or ongoing worsening of pain for about 10 days, and all but two were taking a preventive medication. Nearly 70% had a comorbid psychiatric diagnosis such as anxiety or depression, and 60% had a comorbid chronic pain diagnosis separate from their headache diagnosis.
The primary outcome was percent pain reduction at discharge and headache recurrence within 72 hours, with headache recurrence defined as receipt of neurology care via phone, clinic, or hospital encounter.
Patients received IV ketamine at a median dose of 0.25 mg/kg/hr for a median of 3 days.
Overall, the treatment was “safe and well tolerated,” Dr. Rosenthal said.
There were no serious adverse events and no cardiac side effects; 7% (five out of 68) stopped treatment due to side effects. The most common side effects were dizziness (23%), nausea (16%), blurred vision (12%), hallucinations (19%), cognitive fog (7%), vomiting (6%) and dysphoria (4%), worsening headache (4%), and paresthesia and cramping (1.5%).
‘Exciting Starting Point’
At baseline, pain scores were 8 (on a scale of 0-10) and progressively fell (improved) during treatment. Pain scores were 6 on day 1 and were 5 on day 2, with a slight rebound to 5 at discharge, although the pain reduction at discharge (vs baseline) remained statistically significant (P < .001).
“The median percent pain reduction after 3 days of ketamine was about 40%,” Dr. Rosenthal said.
He noted that on the first day of treatment, 16% of patients responded to treatment (with a > 50% reduction in their initial pain); this doubled to 33% on day 2 and increased to 44% at discharge.
In terms of recurrence, 38% had a recurrence within 1 month, “meaning two thirds did not,” Dr. Rosenthal noted. Median time to recurrence was 7 days. There were no recurrences within 72 hours.
The researchers also tried to tease out which patients might respond best to ketamine.
“Surprisingly,” there wasn’t a strong effect of most demographic variables such as age, sex, gender identity, chronic pain, psychiatric comorbidities, duration of headache, or prior interventions, Dr. Rosenthal noted.
“Interestingly,” he said, patients who were on two or more preventive medications had a 50% reduction in their pain at discharge compared with a 33% reduction in patients taking one or no preventive medication. It’s possible that more preventative medications may “prime” a patient’s response to ketamine, Dr. Rosenthal said.
She added that future randomized studies are needed to further assess IV ketamine for refractory headache in children, but these results are “an exciting starting point.”
‘Still an Unknown’
Seniha Nur Ozudogru, MD, assistant professor of clinical neurology at Penn Medicine in Philadelphia, echoed the need for further study.
The role of IV ketamine in refractory pediatric headache is “still an unknown,” said Dr. Ozudogru, who was not involved in the study.
She noted that currently, there is “no standard protocol for ketamine infusion, even for adults. Every institution has their own protocols, which makes it difficult.”
Dr. Ozudogru also wonders how “doable” in-hospital IV infusions over 3 days may be for children.
“Especially for chronic migraine patients, it can be really tricky to manage expectations in that even if they don’t respond and the headache doesn’t go away, they still may have to be discharged. That requires a specific approach and discussion with the patients,” Dr. Ozudogru said.
Intranasal ketamine is another potential option, she said, with a recent study suggesting that intranasal ketamine is an effective treatment for children hospitalized with refractory migraine.
“However, there is some concern about the potential of addiction and the side effects of hallucinations and what the main protocol will be, so this not a standard treatment and has to be studied further,” she said.
The study had no specific funding. Dr. Rosenthal and Dr. Ozudogru have no relevant disclosures.
A version of this article appeared on Medscape.com.
DENVER — , new research suggests. In a retrospective chart review, IV ketamine led to in a 50% reduction in pain at discharge, with “nearly two-thirds” of patients having no recurrence within 30 days, noted lead investigator Scott Rosenthal, MD, from the University of Colorado Anschutz Medical Campus, Aurora.
Dr. Rosenthal reported the findings at the 2024 annual meeting of the American Academy of Neurology.
Statistically Significant Pain Relief
“IV ketamine has shown benefit in nonheadache chronic pain syndromes and refractory mood disorders. Patients with refractory status migraines are often left with ongoing pain and dysfunction after failing typical interventions,” Dr. Rosenthal said.
“Ketamine has emerged as a potential treatment option in this population. However, there’s very little research on the efficacy and tolerability of it in general as well as the pediatric population,” he noted.
Dr. Rosenthal and colleagues took a look back at patients admitted to Children’s Hospital Colorado between 2019 and 2022 for treatment of severe refractory headache who were treated with continuous IV ketamine.
They analyzed 68 encounters of 41 unique patients aged 5-21 years (median age 16 years; 85% girls). Chronic migraine without aura made up 79% of cases.
On presentation, most patients had an exacerbation or ongoing worsening of pain for about 10 days, and all but two were taking a preventive medication. Nearly 70% had a comorbid psychiatric diagnosis such as anxiety or depression, and 60% had a comorbid chronic pain diagnosis separate from their headache diagnosis.
The primary outcome was percent pain reduction at discharge and headache recurrence within 72 hours, with headache recurrence defined as receipt of neurology care via phone, clinic, or hospital encounter.
Patients received IV ketamine at a median dose of 0.25 mg/kg/hr for a median of 3 days.
Overall, the treatment was “safe and well tolerated,” Dr. Rosenthal said.
There were no serious adverse events and no cardiac side effects; 7% (five out of 68) stopped treatment due to side effects. The most common side effects were dizziness (23%), nausea (16%), blurred vision (12%), hallucinations (19%), cognitive fog (7%), vomiting (6%) and dysphoria (4%), worsening headache (4%), and paresthesia and cramping (1.5%).
‘Exciting Starting Point’
At baseline, pain scores were 8 (on a scale of 0-10) and progressively fell (improved) during treatment. Pain scores were 6 on day 1 and were 5 on day 2, with a slight rebound to 5 at discharge, although the pain reduction at discharge (vs baseline) remained statistically significant (P < .001).
“The median percent pain reduction after 3 days of ketamine was about 40%,” Dr. Rosenthal said.
He noted that on the first day of treatment, 16% of patients responded to treatment (with a > 50% reduction in their initial pain); this doubled to 33% on day 2 and increased to 44% at discharge.
In terms of recurrence, 38% had a recurrence within 1 month, “meaning two thirds did not,” Dr. Rosenthal noted. Median time to recurrence was 7 days. There were no recurrences within 72 hours.
The researchers also tried to tease out which patients might respond best to ketamine.
“Surprisingly,” there wasn’t a strong effect of most demographic variables such as age, sex, gender identity, chronic pain, psychiatric comorbidities, duration of headache, or prior interventions, Dr. Rosenthal noted.
“Interestingly,” he said, patients who were on two or more preventive medications had a 50% reduction in their pain at discharge compared with a 33% reduction in patients taking one or no preventive medication. It’s possible that more preventative medications may “prime” a patient’s response to ketamine, Dr. Rosenthal said.
She added that future randomized studies are needed to further assess IV ketamine for refractory headache in children, but these results are “an exciting starting point.”
‘Still an Unknown’
Seniha Nur Ozudogru, MD, assistant professor of clinical neurology at Penn Medicine in Philadelphia, echoed the need for further study.
The role of IV ketamine in refractory pediatric headache is “still an unknown,” said Dr. Ozudogru, who was not involved in the study.
She noted that currently, there is “no standard protocol for ketamine infusion, even for adults. Every institution has their own protocols, which makes it difficult.”
Dr. Ozudogru also wonders how “doable” in-hospital IV infusions over 3 days may be for children.
“Especially for chronic migraine patients, it can be really tricky to manage expectations in that even if they don’t respond and the headache doesn’t go away, they still may have to be discharged. That requires a specific approach and discussion with the patients,” Dr. Ozudogru said.
Intranasal ketamine is another potential option, she said, with a recent study suggesting that intranasal ketamine is an effective treatment for children hospitalized with refractory migraine.
“However, there is some concern about the potential of addiction and the side effects of hallucinations and what the main protocol will be, so this not a standard treatment and has to be studied further,” she said.
The study had no specific funding. Dr. Rosenthal and Dr. Ozudogru have no relevant disclosures.
A version of this article appeared on Medscape.com.
DENVER — , new research suggests. In a retrospective chart review, IV ketamine led to in a 50% reduction in pain at discharge, with “nearly two-thirds” of patients having no recurrence within 30 days, noted lead investigator Scott Rosenthal, MD, from the University of Colorado Anschutz Medical Campus, Aurora.
Dr. Rosenthal reported the findings at the 2024 annual meeting of the American Academy of Neurology.
Statistically Significant Pain Relief
“IV ketamine has shown benefit in nonheadache chronic pain syndromes and refractory mood disorders. Patients with refractory status migraines are often left with ongoing pain and dysfunction after failing typical interventions,” Dr. Rosenthal said.
“Ketamine has emerged as a potential treatment option in this population. However, there’s very little research on the efficacy and tolerability of it in general as well as the pediatric population,” he noted.
Dr. Rosenthal and colleagues took a look back at patients admitted to Children’s Hospital Colorado between 2019 and 2022 for treatment of severe refractory headache who were treated with continuous IV ketamine.
They analyzed 68 encounters of 41 unique patients aged 5-21 years (median age 16 years; 85% girls). Chronic migraine without aura made up 79% of cases.
On presentation, most patients had an exacerbation or ongoing worsening of pain for about 10 days, and all but two were taking a preventive medication. Nearly 70% had a comorbid psychiatric diagnosis such as anxiety or depression, and 60% had a comorbid chronic pain diagnosis separate from their headache diagnosis.
The primary outcome was percent pain reduction at discharge and headache recurrence within 72 hours, with headache recurrence defined as receipt of neurology care via phone, clinic, or hospital encounter.
Patients received IV ketamine at a median dose of 0.25 mg/kg/hr for a median of 3 days.
Overall, the treatment was “safe and well tolerated,” Dr. Rosenthal said.
There were no serious adverse events and no cardiac side effects; 7% (five out of 68) stopped treatment due to side effects. The most common side effects were dizziness (23%), nausea (16%), blurred vision (12%), hallucinations (19%), cognitive fog (7%), vomiting (6%) and dysphoria (4%), worsening headache (4%), and paresthesia and cramping (1.5%).
‘Exciting Starting Point’
At baseline, pain scores were 8 (on a scale of 0-10) and progressively fell (improved) during treatment. Pain scores were 6 on day 1 and were 5 on day 2, with a slight rebound to 5 at discharge, although the pain reduction at discharge (vs baseline) remained statistically significant (P < .001).
“The median percent pain reduction after 3 days of ketamine was about 40%,” Dr. Rosenthal said.
He noted that on the first day of treatment, 16% of patients responded to treatment (with a > 50% reduction in their initial pain); this doubled to 33% on day 2 and increased to 44% at discharge.
In terms of recurrence, 38% had a recurrence within 1 month, “meaning two thirds did not,” Dr. Rosenthal noted. Median time to recurrence was 7 days. There were no recurrences within 72 hours.
The researchers also tried to tease out which patients might respond best to ketamine.
“Surprisingly,” there wasn’t a strong effect of most demographic variables such as age, sex, gender identity, chronic pain, psychiatric comorbidities, duration of headache, or prior interventions, Dr. Rosenthal noted.
“Interestingly,” he said, patients who were on two or more preventive medications had a 50% reduction in their pain at discharge compared with a 33% reduction in patients taking one or no preventive medication. It’s possible that more preventative medications may “prime” a patient’s response to ketamine, Dr. Rosenthal said.
She added that future randomized studies are needed to further assess IV ketamine for refractory headache in children, but these results are “an exciting starting point.”
‘Still an Unknown’
Seniha Nur Ozudogru, MD, assistant professor of clinical neurology at Penn Medicine in Philadelphia, echoed the need for further study.
The role of IV ketamine in refractory pediatric headache is “still an unknown,” said Dr. Ozudogru, who was not involved in the study.
She noted that currently, there is “no standard protocol for ketamine infusion, even for adults. Every institution has their own protocols, which makes it difficult.”
Dr. Ozudogru also wonders how “doable” in-hospital IV infusions over 3 days may be for children.
“Especially for chronic migraine patients, it can be really tricky to manage expectations in that even if they don’t respond and the headache doesn’t go away, they still may have to be discharged. That requires a specific approach and discussion with the patients,” Dr. Ozudogru said.
Intranasal ketamine is another potential option, she said, with a recent study suggesting that intranasal ketamine is an effective treatment for children hospitalized with refractory migraine.
“However, there is some concern about the potential of addiction and the side effects of hallucinations and what the main protocol will be, so this not a standard treatment and has to be studied further,” she said.
The study had no specific funding. Dr. Rosenthal and Dr. Ozudogru have no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM AAN 2024
First Long-Term Data on Atogepant for Migraine Prevention
DENVER —
The data show that 70% of patients treated with atogepant 60 mg daily achieved at least a 50% reduction in monthly migraine days at weeks 13-16 and this was maintained over 48 weeks of treatment.
“This is the first long-term study for assessing the safety and efficacy of a drug belonging to the gepant class, atogepant, used in the prevention of migraine in persons with episodic migraine who did not benefit from several previous preventive treatments or with chronic migraine,” said study investigator Cristina Tassorelli, MD, professor and chair of neurology, University of Pavia, Italy.
“It shows consistency of efficacy over 48 weeks and confirms the known safety profile of atogepant reported in randomized controlled trials, without detecting any new signal with the open-label use over 1 year,” Dr. Tassorelli said.
The results were reported at the 2024 annual meeting of the American Academy of Neurology by Sait Ashina, MD, with the Comprehensive Headache Center at Beth Israel Deaconess Medical Center in Boston.
Novel Longer-Term Data
The extension study includes more than 500 patients who completed the phase 3 PROGRESS or ELEVATE randomized placebo-controlled trials of atogepant 60 mg once daily for prevention of episodic or chronic migraine. It will run for 156 weeks.
Dr. Ashina reported safety and tolerability data at 52 weeks of treatment and efficacy data between 13 and 48 weeks of treatment. The mean duration of atogepant exposure was 496.5 days, and the mean number of migraine days at baseline was 14.5.
With atogepant, monthly migraine days improved on average by 8.5 days at weeks 13-16, and this was consistent over 48 weeks, Dr. Ashina reported. Similar improvements were observed for monthly headache days and monthly acute medication use days.
In addition, 70% of patients achieved a 50% or greater reduction in monthly migraine days at weeks 13-16, and this was consistent during the 48 weeks of open-label treatment.
Overall safety results were consistent with the known safety profile of atogepant. “A small percentage of subjects (< 6%) discontinue the treatment because of side effects,” Dr. Tassorelli said.
The most common treatment-emergent adverse events (≥ 5% of participants) were COVID-19 (28.7%), nasopharyngitis (10.9%), and constipation (8.2%).
As the first report of 1-year atogepant data, the results are “very encouraging” for patients and clinicians, Dr. Ashina said in wrapping up his presentation.
Important Advance, but Not Transformative
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, noted that “[w]hile the anti-CGRP medications represent an important advancement in migraine treatment, the data suggests they have not necessarily transformed the landscape as dramatically as some may have expected.
“The efficacy of the anti-CGRP drugs appears to be generally similar to previous preventive and mostly genericized treatments, offering modest but meaningful improvements in migraine frequency and severity for many patients,” Dr. Lakhan said.
“In terms of safety, the anti-CGRPs do seem to have a somewhat cleaner profile compared to earlier migraine preventives, which is certainly a positive. However, the long-term data is still emerging, so the full safety picture is not yet clear,” Dr. Lakhan added.
“These medications are also associated with significantly higher overall healthcare costs compared to other treatment approaches. The substantial cost implications, both for patients and the healthcare system, deserve careful consideration as we assess their overall value and role in migraine care going forward,” Dr. Lakhan said.
Funding was provided by AbbVie. Several investigators have disclosed financial relationships with the company. Dr. Lakhan has no relevant disclosures.
A version of this article appeared on Medscape.com.
DENVER —
The data show that 70% of patients treated with atogepant 60 mg daily achieved at least a 50% reduction in monthly migraine days at weeks 13-16 and this was maintained over 48 weeks of treatment.
“This is the first long-term study for assessing the safety and efficacy of a drug belonging to the gepant class, atogepant, used in the prevention of migraine in persons with episodic migraine who did not benefit from several previous preventive treatments or with chronic migraine,” said study investigator Cristina Tassorelli, MD, professor and chair of neurology, University of Pavia, Italy.
“It shows consistency of efficacy over 48 weeks and confirms the known safety profile of atogepant reported in randomized controlled trials, without detecting any new signal with the open-label use over 1 year,” Dr. Tassorelli said.
The results were reported at the 2024 annual meeting of the American Academy of Neurology by Sait Ashina, MD, with the Comprehensive Headache Center at Beth Israel Deaconess Medical Center in Boston.
Novel Longer-Term Data
The extension study includes more than 500 patients who completed the phase 3 PROGRESS or ELEVATE randomized placebo-controlled trials of atogepant 60 mg once daily for prevention of episodic or chronic migraine. It will run for 156 weeks.
Dr. Ashina reported safety and tolerability data at 52 weeks of treatment and efficacy data between 13 and 48 weeks of treatment. The mean duration of atogepant exposure was 496.5 days, and the mean number of migraine days at baseline was 14.5.
With atogepant, monthly migraine days improved on average by 8.5 days at weeks 13-16, and this was consistent over 48 weeks, Dr. Ashina reported. Similar improvements were observed for monthly headache days and monthly acute medication use days.
In addition, 70% of patients achieved a 50% or greater reduction in monthly migraine days at weeks 13-16, and this was consistent during the 48 weeks of open-label treatment.
Overall safety results were consistent with the known safety profile of atogepant. “A small percentage of subjects (< 6%) discontinue the treatment because of side effects,” Dr. Tassorelli said.
The most common treatment-emergent adverse events (≥ 5% of participants) were COVID-19 (28.7%), nasopharyngitis (10.9%), and constipation (8.2%).
As the first report of 1-year atogepant data, the results are “very encouraging” for patients and clinicians, Dr. Ashina said in wrapping up his presentation.
Important Advance, but Not Transformative
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, noted that “[w]hile the anti-CGRP medications represent an important advancement in migraine treatment, the data suggests they have not necessarily transformed the landscape as dramatically as some may have expected.
“The efficacy of the anti-CGRP drugs appears to be generally similar to previous preventive and mostly genericized treatments, offering modest but meaningful improvements in migraine frequency and severity for many patients,” Dr. Lakhan said.
“In terms of safety, the anti-CGRPs do seem to have a somewhat cleaner profile compared to earlier migraine preventives, which is certainly a positive. However, the long-term data is still emerging, so the full safety picture is not yet clear,” Dr. Lakhan added.
“These medications are also associated with significantly higher overall healthcare costs compared to other treatment approaches. The substantial cost implications, both for patients and the healthcare system, deserve careful consideration as we assess their overall value and role in migraine care going forward,” Dr. Lakhan said.
Funding was provided by AbbVie. Several investigators have disclosed financial relationships with the company. Dr. Lakhan has no relevant disclosures.
A version of this article appeared on Medscape.com.
DENVER —
The data show that 70% of patients treated with atogepant 60 mg daily achieved at least a 50% reduction in monthly migraine days at weeks 13-16 and this was maintained over 48 weeks of treatment.
“This is the first long-term study for assessing the safety and efficacy of a drug belonging to the gepant class, atogepant, used in the prevention of migraine in persons with episodic migraine who did not benefit from several previous preventive treatments or with chronic migraine,” said study investigator Cristina Tassorelli, MD, professor and chair of neurology, University of Pavia, Italy.
“It shows consistency of efficacy over 48 weeks and confirms the known safety profile of atogepant reported in randomized controlled trials, without detecting any new signal with the open-label use over 1 year,” Dr. Tassorelli said.
The results were reported at the 2024 annual meeting of the American Academy of Neurology by Sait Ashina, MD, with the Comprehensive Headache Center at Beth Israel Deaconess Medical Center in Boston.
Novel Longer-Term Data
The extension study includes more than 500 patients who completed the phase 3 PROGRESS or ELEVATE randomized placebo-controlled trials of atogepant 60 mg once daily for prevention of episodic or chronic migraine. It will run for 156 weeks.
Dr. Ashina reported safety and tolerability data at 52 weeks of treatment and efficacy data between 13 and 48 weeks of treatment. The mean duration of atogepant exposure was 496.5 days, and the mean number of migraine days at baseline was 14.5.
With atogepant, monthly migraine days improved on average by 8.5 days at weeks 13-16, and this was consistent over 48 weeks, Dr. Ashina reported. Similar improvements were observed for monthly headache days and monthly acute medication use days.
In addition, 70% of patients achieved a 50% or greater reduction in monthly migraine days at weeks 13-16, and this was consistent during the 48 weeks of open-label treatment.
Overall safety results were consistent with the known safety profile of atogepant. “A small percentage of subjects (< 6%) discontinue the treatment because of side effects,” Dr. Tassorelli said.
The most common treatment-emergent adverse events (≥ 5% of participants) were COVID-19 (28.7%), nasopharyngitis (10.9%), and constipation (8.2%).
As the first report of 1-year atogepant data, the results are “very encouraging” for patients and clinicians, Dr. Ashina said in wrapping up his presentation.
Important Advance, but Not Transformative
Reached for comment, Shaheen Lakhan, MD, a neurologist and researcher based in Miami, noted that “[w]hile the anti-CGRP medications represent an important advancement in migraine treatment, the data suggests they have not necessarily transformed the landscape as dramatically as some may have expected.
“The efficacy of the anti-CGRP drugs appears to be generally similar to previous preventive and mostly genericized treatments, offering modest but meaningful improvements in migraine frequency and severity for many patients,” Dr. Lakhan said.
“In terms of safety, the anti-CGRPs do seem to have a somewhat cleaner profile compared to earlier migraine preventives, which is certainly a positive. However, the long-term data is still emerging, so the full safety picture is not yet clear,” Dr. Lakhan added.
“These medications are also associated with significantly higher overall healthcare costs compared to other treatment approaches. The substantial cost implications, both for patients and the healthcare system, deserve careful consideration as we assess their overall value and role in migraine care going forward,” Dr. Lakhan said.
Funding was provided by AbbVie. Several investigators have disclosed financial relationships with the company. Dr. Lakhan has no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM AAN 2024
Tension, Other Headache Types Robustly Linked to Attempted, Completed Suicide
DENVER – , results of a large study suggest.
The risk for suicide attempt was four times higher in people with trigeminal and autonomic cephalalgias (TAC), and the risk for completed suicide was double among those with posttraumatic headache compared with individuals with no headache.
The retrospective analysis included data on more than 100,000 headache patients from a Danish registry.
“The results suggest there’s a unique risk among headache patients for attempted and completed suicide,” lead investigator Holly Elser, MD, MPH, PhD, resident, Department of Neurology, University of Pennsylvania, Philadelphia, said at the 2024 annual meeting of the American Academy of Neurology, where the findings were presented. “This really underscores the potential importance of complementary psychiatric evaluation and treatment for individuals diagnosed with headache.”
Underestimated Problem
Headache disorders affect about half of working-age adults and are among the leading causes of productivity loss, absence from work, and disability.
Prior research suggests headache disorders often co-occur with psychiatric illness including depression, anxiety, posttraumatic stress disorder, and even attempted suicide.
However, previous studies that showed an increased risk for attempted suicide in patients with headache relied heavily on survey data and mostly focused on patients with migraine. There was little information on other headache types and on the risk for completed suicide.
Researchers used Danish registries to identify 64,057 patients with migraine, 40,160 with tension-type headache (TTH), 5743 with TAC, and 4253 with posttraumatic headache, all diagnosed from 1995 to 2019.
Some 5.8% of those with migraine, 6.3% with TAC, 7.2% with TTH, and 7.2% with posttraumatic headache, had a mood disorder (depression and anxiety combined) at baseline.
Those without a headache diagnosis were matched 5:1 to those with a headache diagnosis by sex and birth year.
Across all headache disorders, baseline prevalence of mood disorder was higher among those with headache versus population-matched controls. Dr. Elser emphasized that these are people diagnosed with a mood disorder in the inpatient, emergency department, or outpatient specialist clinic setting, “which means we are almost certainly underestimating the true burden of mood symptoms in our cohort,” she said.
Researchers identified attempted suicides using diagnostic codes. For completed suicide, they determined whether those who attempted suicide died within 30 days of the attempt.
For each headache type, investigators examined both the absolute and relative risk for attempted and completed suicides and estimated the risk at intervals of 5, 10, and 20 years after initial headache diagnosis.
Robust Link
The “power of this study is that we asked a simple, but important question, and answered it with simple, but appropriate, methodologic techniques,” Dr. Elser said.
The estimated risk differences (RDs) for attempted suicide were strongest for TAC and posttraumatic headache and for longer follow-ups. The RDs for completed suicide were largely the same but of a smaller magnitude and were “relatively less precise,” reflecting the “rarity of this outcome,” said Dr. Elser.
After adjusting for sex, age, education, income, comorbidities, and baseline medical and psychiatric diagnoses, researchers found the strongest association or attempted suicide was among those with TAC (adjusted hazard ratio [aHR], 4.25; 95% CI, 2.85-6.33).
“A hazard ratio of 4 is enormous” for this type of comparison, Dr. Elser noted.
For completed suicide, the strongest association was with posttraumatic headache (aHR, 2.19; 95% CI, 0.78-6.16).
The study revealed a robust association with attempted and completed suicide across all headache types, including TTH, noted Dr. Elser. The link between tension headaches and suicide “was the most striking finding to me because I think of that as sort of a benign and common headache disorder,” she said.
The was an observational study, so “it’s not clear whether headache is playing an etiological role in the relationship with suicide,” she said. “It’s possible there are common shared risk factors or confounders that explain the relationship in full or in part that aren’t accounted for in this study.”
Ask About Mood
The results underscore the need for psychiatric evaluations in patients with a headache disorder. “For me, this is just going to make me that much more likely to ask my patients about their mood when I see them in clinic,” Dr. Elser said.
After asking patients with headache about their mood and stress at home and at work, physicians should have a “low threshold to refer to a behavioral health provider,” she added.
Future research should aim to better understand the link between headache and suicide risk, with a focus on the mechanisms behind low- and high-risk subgroups, said Dr. Elser.
A limitation of the study was that headache diagnoses were based on inpatient, emergency department, and outpatient specialist visits but not on visits to primary care practitioners. The study didn’t include information on headache severity or frequency and included only people who sought treatment for their headaches.
Though it’s unlikely the results “are perfectly generalizable” with respect to other geographical or cultural contexts, “I don’t think this relationship is unique to Denmark based on the literature to date,” Dr. Elser said.
Commenting on the study, session co-chair Todd J. Schwedt, MD, professor of neurology, Mayo Clinic Arizona, Phoenix, and president-elect of the American Headache Society, noted that the study offers important findings “that demonstrate the enormous negative impact that headaches can exert.”
It’s “a strong reminder” that clinicians should assess the mental health of their patients with headaches and offer treatment when appropriate, he said.
The study received support from Aarhus University. No relevant conflicts of interest were reported.
A version of this article appeared on Medscape.com.
DENVER – , results of a large study suggest.
The risk for suicide attempt was four times higher in people with trigeminal and autonomic cephalalgias (TAC), and the risk for completed suicide was double among those with posttraumatic headache compared with individuals with no headache.
The retrospective analysis included data on more than 100,000 headache patients from a Danish registry.
“The results suggest there’s a unique risk among headache patients for attempted and completed suicide,” lead investigator Holly Elser, MD, MPH, PhD, resident, Department of Neurology, University of Pennsylvania, Philadelphia, said at the 2024 annual meeting of the American Academy of Neurology, where the findings were presented. “This really underscores the potential importance of complementary psychiatric evaluation and treatment for individuals diagnosed with headache.”
Underestimated Problem
Headache disorders affect about half of working-age adults and are among the leading causes of productivity loss, absence from work, and disability.
Prior research suggests headache disorders often co-occur with psychiatric illness including depression, anxiety, posttraumatic stress disorder, and even attempted suicide.
However, previous studies that showed an increased risk for attempted suicide in patients with headache relied heavily on survey data and mostly focused on patients with migraine. There was little information on other headache types and on the risk for completed suicide.
Researchers used Danish registries to identify 64,057 patients with migraine, 40,160 with tension-type headache (TTH), 5743 with TAC, and 4253 with posttraumatic headache, all diagnosed from 1995 to 2019.
Some 5.8% of those with migraine, 6.3% with TAC, 7.2% with TTH, and 7.2% with posttraumatic headache, had a mood disorder (depression and anxiety combined) at baseline.
Those without a headache diagnosis were matched 5:1 to those with a headache diagnosis by sex and birth year.
Across all headache disorders, baseline prevalence of mood disorder was higher among those with headache versus population-matched controls. Dr. Elser emphasized that these are people diagnosed with a mood disorder in the inpatient, emergency department, or outpatient specialist clinic setting, “which means we are almost certainly underestimating the true burden of mood symptoms in our cohort,” she said.
Researchers identified attempted suicides using diagnostic codes. For completed suicide, they determined whether those who attempted suicide died within 30 days of the attempt.
For each headache type, investigators examined both the absolute and relative risk for attempted and completed suicides and estimated the risk at intervals of 5, 10, and 20 years after initial headache diagnosis.
Robust Link
The “power of this study is that we asked a simple, but important question, and answered it with simple, but appropriate, methodologic techniques,” Dr. Elser said.
The estimated risk differences (RDs) for attempted suicide were strongest for TAC and posttraumatic headache and for longer follow-ups. The RDs for completed suicide were largely the same but of a smaller magnitude and were “relatively less precise,” reflecting the “rarity of this outcome,” said Dr. Elser.
After adjusting for sex, age, education, income, comorbidities, and baseline medical and psychiatric diagnoses, researchers found the strongest association or attempted suicide was among those with TAC (adjusted hazard ratio [aHR], 4.25; 95% CI, 2.85-6.33).
“A hazard ratio of 4 is enormous” for this type of comparison, Dr. Elser noted.
For completed suicide, the strongest association was with posttraumatic headache (aHR, 2.19; 95% CI, 0.78-6.16).
The study revealed a robust association with attempted and completed suicide across all headache types, including TTH, noted Dr. Elser. The link between tension headaches and suicide “was the most striking finding to me because I think of that as sort of a benign and common headache disorder,” she said.
The was an observational study, so “it’s not clear whether headache is playing an etiological role in the relationship with suicide,” she said. “It’s possible there are common shared risk factors or confounders that explain the relationship in full or in part that aren’t accounted for in this study.”
Ask About Mood
The results underscore the need for psychiatric evaluations in patients with a headache disorder. “For me, this is just going to make me that much more likely to ask my patients about their mood when I see them in clinic,” Dr. Elser said.
After asking patients with headache about their mood and stress at home and at work, physicians should have a “low threshold to refer to a behavioral health provider,” she added.
Future research should aim to better understand the link between headache and suicide risk, with a focus on the mechanisms behind low- and high-risk subgroups, said Dr. Elser.
A limitation of the study was that headache diagnoses were based on inpatient, emergency department, and outpatient specialist visits but not on visits to primary care practitioners. The study didn’t include information on headache severity or frequency and included only people who sought treatment for their headaches.
Though it’s unlikely the results “are perfectly generalizable” with respect to other geographical or cultural contexts, “I don’t think this relationship is unique to Denmark based on the literature to date,” Dr. Elser said.
Commenting on the study, session co-chair Todd J. Schwedt, MD, professor of neurology, Mayo Clinic Arizona, Phoenix, and president-elect of the American Headache Society, noted that the study offers important findings “that demonstrate the enormous negative impact that headaches can exert.”
It’s “a strong reminder” that clinicians should assess the mental health of their patients with headaches and offer treatment when appropriate, he said.
The study received support from Aarhus University. No relevant conflicts of interest were reported.
A version of this article appeared on Medscape.com.
DENVER – , results of a large study suggest.
The risk for suicide attempt was four times higher in people with trigeminal and autonomic cephalalgias (TAC), and the risk for completed suicide was double among those with posttraumatic headache compared with individuals with no headache.
The retrospective analysis included data on more than 100,000 headache patients from a Danish registry.
“The results suggest there’s a unique risk among headache patients for attempted and completed suicide,” lead investigator Holly Elser, MD, MPH, PhD, resident, Department of Neurology, University of Pennsylvania, Philadelphia, said at the 2024 annual meeting of the American Academy of Neurology, where the findings were presented. “This really underscores the potential importance of complementary psychiatric evaluation and treatment for individuals diagnosed with headache.”
Underestimated Problem
Headache disorders affect about half of working-age adults and are among the leading causes of productivity loss, absence from work, and disability.
Prior research suggests headache disorders often co-occur with psychiatric illness including depression, anxiety, posttraumatic stress disorder, and even attempted suicide.
However, previous studies that showed an increased risk for attempted suicide in patients with headache relied heavily on survey data and mostly focused on patients with migraine. There was little information on other headache types and on the risk for completed suicide.
Researchers used Danish registries to identify 64,057 patients with migraine, 40,160 with tension-type headache (TTH), 5743 with TAC, and 4253 with posttraumatic headache, all diagnosed from 1995 to 2019.
Some 5.8% of those with migraine, 6.3% with TAC, 7.2% with TTH, and 7.2% with posttraumatic headache, had a mood disorder (depression and anxiety combined) at baseline.
Those without a headache diagnosis were matched 5:1 to those with a headache diagnosis by sex and birth year.
Across all headache disorders, baseline prevalence of mood disorder was higher among those with headache versus population-matched controls. Dr. Elser emphasized that these are people diagnosed with a mood disorder in the inpatient, emergency department, or outpatient specialist clinic setting, “which means we are almost certainly underestimating the true burden of mood symptoms in our cohort,” she said.
Researchers identified attempted suicides using diagnostic codes. For completed suicide, they determined whether those who attempted suicide died within 30 days of the attempt.
For each headache type, investigators examined both the absolute and relative risk for attempted and completed suicides and estimated the risk at intervals of 5, 10, and 20 years after initial headache diagnosis.
Robust Link
The “power of this study is that we asked a simple, but important question, and answered it with simple, but appropriate, methodologic techniques,” Dr. Elser said.
The estimated risk differences (RDs) for attempted suicide were strongest for TAC and posttraumatic headache and for longer follow-ups. The RDs for completed suicide were largely the same but of a smaller magnitude and were “relatively less precise,” reflecting the “rarity of this outcome,” said Dr. Elser.
After adjusting for sex, age, education, income, comorbidities, and baseline medical and psychiatric diagnoses, researchers found the strongest association or attempted suicide was among those with TAC (adjusted hazard ratio [aHR], 4.25; 95% CI, 2.85-6.33).
“A hazard ratio of 4 is enormous” for this type of comparison, Dr. Elser noted.
For completed suicide, the strongest association was with posttraumatic headache (aHR, 2.19; 95% CI, 0.78-6.16).
The study revealed a robust association with attempted and completed suicide across all headache types, including TTH, noted Dr. Elser. The link between tension headaches and suicide “was the most striking finding to me because I think of that as sort of a benign and common headache disorder,” she said.
The was an observational study, so “it’s not clear whether headache is playing an etiological role in the relationship with suicide,” she said. “It’s possible there are common shared risk factors or confounders that explain the relationship in full or in part that aren’t accounted for in this study.”
Ask About Mood
The results underscore the need for psychiatric evaluations in patients with a headache disorder. “For me, this is just going to make me that much more likely to ask my patients about their mood when I see them in clinic,” Dr. Elser said.
After asking patients with headache about their mood and stress at home and at work, physicians should have a “low threshold to refer to a behavioral health provider,” she added.
Future research should aim to better understand the link between headache and suicide risk, with a focus on the mechanisms behind low- and high-risk subgroups, said Dr. Elser.
A limitation of the study was that headache diagnoses were based on inpatient, emergency department, and outpatient specialist visits but not on visits to primary care practitioners. The study didn’t include information on headache severity or frequency and included only people who sought treatment for their headaches.
Though it’s unlikely the results “are perfectly generalizable” with respect to other geographical or cultural contexts, “I don’t think this relationship is unique to Denmark based on the literature to date,” Dr. Elser said.
Commenting on the study, session co-chair Todd J. Schwedt, MD, professor of neurology, Mayo Clinic Arizona, Phoenix, and president-elect of the American Headache Society, noted that the study offers important findings “that demonstrate the enormous negative impact that headaches can exert.”
It’s “a strong reminder” that clinicians should assess the mental health of their patients with headaches and offer treatment when appropriate, he said.
The study received support from Aarhus University. No relevant conflicts of interest were reported.
A version of this article appeared on Medscape.com.
FROM AAN 2024
‘Compelling’ Results for AI EEG to Predict Functional Outcomes
DENVER —
After relevant cofactors were controlled for, higher seizure burden correlated with poorer functional outcomes. All of the patients in the study were being monitored as part of their standard of care owing to suspicion of seizures or because they were at risk for seizures, said study investigator Masoom Desai, MD, with the Department of Neurology, University of New Mexico, Albuquerque. The results were “compelling,” she said.
“Our study addresses the critical need for automation in monitoring epileptic activity and seizure burden,” Dr. Desai added during a press briefing at the 2024 annual meeting of the American Academy of Neurology (AAN).
A Pivotal Shift
“Several decades of research have highlighted the significant correlation between seizure burden and unfavorable outcomes both in adult and pediatric populations,” said Dr. Desai.
However, the traditional method of manually interpreting EEGs to identify seizures and their associated burden is a “complex and time-consuming process that can be subject to human error and variability,” she noted.
POC EEG is a rapid-access, reduced-montage EEG system that, when paired with an automated machine learning tool called Clarity (Ceribell, Inc; Sunnyvale, CA), can monitor and analyze seizure burden in real time.
The algorithm incorporates a comprehensive list of EEG features that have been associated with outcomes. It analyzes EEG activity every 10 seconds from all EEG channels and calculates a seizure burden in the past 5 minutes for the patient. The higher the seizure burden, the more time the patient has spent in seizure activity.
Among 344 people with POC EEG (mean age, 62 years, 45% women) in the SAFER-EEG trial, 178 (52%) had seizure burden of zero throughout the recording and 41 (12%) had suspected status epilepticus (maximum seizure burden ≥ 90%).
Before adjustment for clinical covariates, there was a significant association between high seizure burden and unfavorable outcomes.
Specifically, 76% of patients with a seizure burden of 50% or greater had an unfavorable modified Rankin Scale score of 4 or greater at discharge and a similar proportion was discharged to long-term care facilities, she noted.
After adjustment for relevant clinical covariants, patients with a high seizure burden (≥ 50 or > 90%) had a fourfold increase in odds of an unfavorable modified Rankin Scale score compared with those with no seizure burden.
High seizure burden present in the last quarter of the recording was particularly indicative of unfavorable outcomes (fivefold increased odds), “suggesting the critical timing of seizures and its impact on patient prognosis,” Dr. Desai noted.
‘Profound Implications’
“The implications of our research are profound, indicating a pivotal shift towards integrating AI and machine learning-guided automated EEG interpretation in management of critically ill patients with seizures,” she added.
“As we move forward, our research will concentrate on applying this advanced tool in clinical decision making in clinical practice, examining how it can steer treatment decisions for patients, with the ultimate goal of enhancing patient care and improving outcomes for those affected by these neurological challenges,” Dr. Desai said.
Briefing moderator Paul M. George, MD, PhD, chair of the AAN science committee, noted that this abstract was one of three featured at the “top science” press briefing themed “advancing the limits of neurologic care,” because it represents an “innovative method” of using new technology to improve understanding of neurologic conditions.
Dr. George said this technology “could be particularly useful in settings with few clinical specialists. It will be exciting to see as this unfolds, where it can guide maybe the ED doctor or primary care physician to help improve patient care.”
On that note, Dr. George cautioned that it’s still “early in the field” of using AI to guide decision-making and it will be important to gather more information to confirm that “machine learning algorithms can help guide physicians in treating patients with neurologic conditions.”
Funding for the study was provided by the University of Wisconsin-Madison and Ceribell, Inc. Dr. Desai received funding from Ceribell for this project. Dr. George has no relevant disclosures.
A version of this article appeared on Medscape.com.
DENVER —
After relevant cofactors were controlled for, higher seizure burden correlated with poorer functional outcomes. All of the patients in the study were being monitored as part of their standard of care owing to suspicion of seizures or because they were at risk for seizures, said study investigator Masoom Desai, MD, with the Department of Neurology, University of New Mexico, Albuquerque. The results were “compelling,” she said.
“Our study addresses the critical need for automation in monitoring epileptic activity and seizure burden,” Dr. Desai added during a press briefing at the 2024 annual meeting of the American Academy of Neurology (AAN).
A Pivotal Shift
“Several decades of research have highlighted the significant correlation between seizure burden and unfavorable outcomes both in adult and pediatric populations,” said Dr. Desai.
However, the traditional method of manually interpreting EEGs to identify seizures and their associated burden is a “complex and time-consuming process that can be subject to human error and variability,” she noted.
POC EEG is a rapid-access, reduced-montage EEG system that, when paired with an automated machine learning tool called Clarity (Ceribell, Inc; Sunnyvale, CA), can monitor and analyze seizure burden in real time.
The algorithm incorporates a comprehensive list of EEG features that have been associated with outcomes. It analyzes EEG activity every 10 seconds from all EEG channels and calculates a seizure burden in the past 5 minutes for the patient. The higher the seizure burden, the more time the patient has spent in seizure activity.
Among 344 people with POC EEG (mean age, 62 years, 45% women) in the SAFER-EEG trial, 178 (52%) had seizure burden of zero throughout the recording and 41 (12%) had suspected status epilepticus (maximum seizure burden ≥ 90%).
Before adjustment for clinical covariates, there was a significant association between high seizure burden and unfavorable outcomes.
Specifically, 76% of patients with a seizure burden of 50% or greater had an unfavorable modified Rankin Scale score of 4 or greater at discharge and a similar proportion was discharged to long-term care facilities, she noted.
After adjustment for relevant clinical covariants, patients with a high seizure burden (≥ 50 or > 90%) had a fourfold increase in odds of an unfavorable modified Rankin Scale score compared with those with no seizure burden.
High seizure burden present in the last quarter of the recording was particularly indicative of unfavorable outcomes (fivefold increased odds), “suggesting the critical timing of seizures and its impact on patient prognosis,” Dr. Desai noted.
‘Profound Implications’
“The implications of our research are profound, indicating a pivotal shift towards integrating AI and machine learning-guided automated EEG interpretation in management of critically ill patients with seizures,” she added.
“As we move forward, our research will concentrate on applying this advanced tool in clinical decision making in clinical practice, examining how it can steer treatment decisions for patients, with the ultimate goal of enhancing patient care and improving outcomes for those affected by these neurological challenges,” Dr. Desai said.
Briefing moderator Paul M. George, MD, PhD, chair of the AAN science committee, noted that this abstract was one of three featured at the “top science” press briefing themed “advancing the limits of neurologic care,” because it represents an “innovative method” of using new technology to improve understanding of neurologic conditions.
Dr. George said this technology “could be particularly useful in settings with few clinical specialists. It will be exciting to see as this unfolds, where it can guide maybe the ED doctor or primary care physician to help improve patient care.”
On that note, Dr. George cautioned that it’s still “early in the field” of using AI to guide decision-making and it will be important to gather more information to confirm that “machine learning algorithms can help guide physicians in treating patients with neurologic conditions.”
Funding for the study was provided by the University of Wisconsin-Madison and Ceribell, Inc. Dr. Desai received funding from Ceribell for this project. Dr. George has no relevant disclosures.
A version of this article appeared on Medscape.com.
DENVER —
After relevant cofactors were controlled for, higher seizure burden correlated with poorer functional outcomes. All of the patients in the study were being monitored as part of their standard of care owing to suspicion of seizures or because they were at risk for seizures, said study investigator Masoom Desai, MD, with the Department of Neurology, University of New Mexico, Albuquerque. The results were “compelling,” she said.
“Our study addresses the critical need for automation in monitoring epileptic activity and seizure burden,” Dr. Desai added during a press briefing at the 2024 annual meeting of the American Academy of Neurology (AAN).
A Pivotal Shift
“Several decades of research have highlighted the significant correlation between seizure burden and unfavorable outcomes both in adult and pediatric populations,” said Dr. Desai.
However, the traditional method of manually interpreting EEGs to identify seizures and their associated burden is a “complex and time-consuming process that can be subject to human error and variability,” she noted.
POC EEG is a rapid-access, reduced-montage EEG system that, when paired with an automated machine learning tool called Clarity (Ceribell, Inc; Sunnyvale, CA), can monitor and analyze seizure burden in real time.
The algorithm incorporates a comprehensive list of EEG features that have been associated with outcomes. It analyzes EEG activity every 10 seconds from all EEG channels and calculates a seizure burden in the past 5 minutes for the patient. The higher the seizure burden, the more time the patient has spent in seizure activity.
Among 344 people with POC EEG (mean age, 62 years, 45% women) in the SAFER-EEG trial, 178 (52%) had seizure burden of zero throughout the recording and 41 (12%) had suspected status epilepticus (maximum seizure burden ≥ 90%).
Before adjustment for clinical covariates, there was a significant association between high seizure burden and unfavorable outcomes.
Specifically, 76% of patients with a seizure burden of 50% or greater had an unfavorable modified Rankin Scale score of 4 or greater at discharge and a similar proportion was discharged to long-term care facilities, she noted.
After adjustment for relevant clinical covariants, patients with a high seizure burden (≥ 50 or > 90%) had a fourfold increase in odds of an unfavorable modified Rankin Scale score compared with those with no seizure burden.
High seizure burden present in the last quarter of the recording was particularly indicative of unfavorable outcomes (fivefold increased odds), “suggesting the critical timing of seizures and its impact on patient prognosis,” Dr. Desai noted.
‘Profound Implications’
“The implications of our research are profound, indicating a pivotal shift towards integrating AI and machine learning-guided automated EEG interpretation in management of critically ill patients with seizures,” she added.
“As we move forward, our research will concentrate on applying this advanced tool in clinical decision making in clinical practice, examining how it can steer treatment decisions for patients, with the ultimate goal of enhancing patient care and improving outcomes for those affected by these neurological challenges,” Dr. Desai said.
Briefing moderator Paul M. George, MD, PhD, chair of the AAN science committee, noted that this abstract was one of three featured at the “top science” press briefing themed “advancing the limits of neurologic care,” because it represents an “innovative method” of using new technology to improve understanding of neurologic conditions.
Dr. George said this technology “could be particularly useful in settings with few clinical specialists. It will be exciting to see as this unfolds, where it can guide maybe the ED doctor or primary care physician to help improve patient care.”
On that note, Dr. George cautioned that it’s still “early in the field” of using AI to guide decision-making and it will be important to gather more information to confirm that “machine learning algorithms can help guide physicians in treating patients with neurologic conditions.”
Funding for the study was provided by the University of Wisconsin-Madison and Ceribell, Inc. Dr. Desai received funding from Ceribell for this project. Dr. George has no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM AAN 2024
In Lecanemab Alzheimer Extension Study, Placebo Roll-Over Group Does Not Catch Up
DENVER — , according to a first report of 6-month OLE data.
Due to the steady disease progression observed after the switch of placebo to active therapy, the message of these data is that “early initiation of lecanemab is important,” according to Michael Irizarry, MD, the senior vice president of clinical research at Eisai Ltd, which markets lecanemab.
The 6-month OLE data along with data from a tau PET substudy were presented by Dr. Irizarry at the 2024 annual meeting of the American Academy of Neurology.
From the start of the OLE through the 6-month follow-up, the downward trajectory of cognitive function, as measured with the Clinical Dementia Rating – Sum of Boxes (CDR-SB), has been parallel for the lecanemab-start and switch arms. As a result, the degree of separation between active and placebo groups over the course of the OLE has remained unchanged from the end of the randomized trial.
This does not rule out any benefit in the switch arm, according to Dr. Irizarry. Although there was no discernible change in the trajectory of decline among placebo patients after they were switched to lecanemab, Dr. Irizarry postulated that this might overlook the greater likely decline over time with no treatment.
“There was no placebo group in the OLE to compare with those on active treatment,” he pointed out. He then juxtaposed data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Over the same 6-month timeframe, these data show a hypothetical separation of the curves if no treatment had been received.
The 6-month OLE data provide a preliminary look at outcomes in a planned 4-year follow-up. At the end of the randomized CLARITY trial, the mean decline from the baseline CDR-SB score of 3.2, was 1.21 in the lecanemab group, translating into a 38% decline, and 1.66 in the placebo group, translating into about a 50% decline. Over the 6 months of OLE, there has been a further mean CDR-SB reduction of approximately 0.6 in both arms, suggesting a further 18% decline from baseline.
Additional Data
In the pivotal CLARITY trial, which was published a few months prior to regulatory approval early last year, 1785 patients were randomized to 10 mg/kg lecanemab or placebo infused every 2 weeks. At the end of 18 months, the superiority of lecanemab for the primary endpoint of adverse change in CDR-SB was highly significant (P < .001) as were the differences in key secondary endpoints, such as Alzheimer’s Disease Composite Score (P < .001).
Of those who participated in CLARITY, 1385 patients entered the OLE. Placebo patients were switched to lecanemab which is being maintained in all patients on the trial schedule of 10 mg/kg administered by intravenous infusion every 2 weeks.
In addition to the overall OLE 6-month data, which has not raised any new safety signals, Dr. Irizarry provided a new look at the PET TAU substudy with a focus on patients who entered the study with a low relative tau burden. Of the three classifications, which also included medium and high tau, as measured with positron-emission tomography (PET), the low tau group represented 41.2% of the 342 tau PET substudy participants. With only 2.9% entering the study with a high tau burden, almost all the others fell in the medium stratification.
Due to the potential for a lower therapeutic response, “patients with low Tau are often excluded from trials,” Dr. Irizarry said. But the sizable proportion of low tau patients has permitted an assessment of relative response with lecanemab, which turned out to be substantial.
“Consistent rates of clinical stability or improvements were observed regardless of baseline tau levels with the highest rates of improvements observed for the low tau group after 24 months of follow-up,” Dr. Irizarry reported.
In previously reported results from the tau PET substudy, lecanemab was shown to slow tau spread at least numerically in every section of the brain evaluated, including the frontal, cingulate, parietal, and whole cortical gray matter areas. The reductions reached significance for the medial temporal (P = .0024), meta temporal (P = .012), and temporal (P = .16) portions.
When most recently evaluated in the OLE, the CDR-SB score declined 38% less among those treated with lecanemab than those treated with placebo in the subgroup enrolled in the tau PET substudy.
Relative to those with intermediate or high tau, patients in the low tau had an even greater reduction in cognitive decline than those with higher tau burdens. Although Dr. Irizarry cautioned that greater baseline CDR-SB scores exaggerated the treatment effect in the low tau group, the message is that “a lecanemab treatment effect is seen even when baseline tau levels are low.”
Now, with the recent market withdrawal of aducanumab, another anti-amyloid monoclonal antibody that was previously approved for Alzheimer’s disease, lecanemab is the only therapy currently available for the goal of changing disease progression, not just modifying symptoms.
Looking Long Term
Both sets of data provide important messages for clinicians, according to Marcelo Matiello, MD, a physician investigator at Mass General Hospital and associate professor of neurology at Harvard Medical School, Boston.
“Clinicians are really looking for more data because this remains a relatively new drug,” he said. Both sets of findings presented by Dr. Irizarry “look good but the follow-up is still short, so I think everyone is still looking closely at long-term safety and efficacy.”
The need for continuous indefinite therapy is one concern that Dr. Matiello expressed. As moderator of the session in which these data were presented, Dr. Matiello specifically asked Dr. Irizarry if there are plans to explore whether periods without treatment might be a means to reduce the cost and burden of frequent infusions while preserving cognitive gains.
In response, Dr. Irizarry said that earlier studies showed rapid progression when lecanemab was stopped. On this basis, he thinks therapy must be maintained, but he did say that there are plans to look at less frequent dosing, such as once per month. He also said that a subcutaneous formulation in development might also reduce the burden of prolonged treatment.
Dr. Irizarry is an employee of Eisai Ltd., which manufacturers lecanemab. Dr. Matiello reports no potential conflicts of interest.
DENVER — , according to a first report of 6-month OLE data.
Due to the steady disease progression observed after the switch of placebo to active therapy, the message of these data is that “early initiation of lecanemab is important,” according to Michael Irizarry, MD, the senior vice president of clinical research at Eisai Ltd, which markets lecanemab.
The 6-month OLE data along with data from a tau PET substudy were presented by Dr. Irizarry at the 2024 annual meeting of the American Academy of Neurology.
From the start of the OLE through the 6-month follow-up, the downward trajectory of cognitive function, as measured with the Clinical Dementia Rating – Sum of Boxes (CDR-SB), has been parallel for the lecanemab-start and switch arms. As a result, the degree of separation between active and placebo groups over the course of the OLE has remained unchanged from the end of the randomized trial.
This does not rule out any benefit in the switch arm, according to Dr. Irizarry. Although there was no discernible change in the trajectory of decline among placebo patients after they were switched to lecanemab, Dr. Irizarry postulated that this might overlook the greater likely decline over time with no treatment.
“There was no placebo group in the OLE to compare with those on active treatment,” he pointed out. He then juxtaposed data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Over the same 6-month timeframe, these data show a hypothetical separation of the curves if no treatment had been received.
The 6-month OLE data provide a preliminary look at outcomes in a planned 4-year follow-up. At the end of the randomized CLARITY trial, the mean decline from the baseline CDR-SB score of 3.2, was 1.21 in the lecanemab group, translating into a 38% decline, and 1.66 in the placebo group, translating into about a 50% decline. Over the 6 months of OLE, there has been a further mean CDR-SB reduction of approximately 0.6 in both arms, suggesting a further 18% decline from baseline.
Additional Data
In the pivotal CLARITY trial, which was published a few months prior to regulatory approval early last year, 1785 patients were randomized to 10 mg/kg lecanemab or placebo infused every 2 weeks. At the end of 18 months, the superiority of lecanemab for the primary endpoint of adverse change in CDR-SB was highly significant (P < .001) as were the differences in key secondary endpoints, such as Alzheimer’s Disease Composite Score (P < .001).
Of those who participated in CLARITY, 1385 patients entered the OLE. Placebo patients were switched to lecanemab which is being maintained in all patients on the trial schedule of 10 mg/kg administered by intravenous infusion every 2 weeks.
In addition to the overall OLE 6-month data, which has not raised any new safety signals, Dr. Irizarry provided a new look at the PET TAU substudy with a focus on patients who entered the study with a low relative tau burden. Of the three classifications, which also included medium and high tau, as measured with positron-emission tomography (PET), the low tau group represented 41.2% of the 342 tau PET substudy participants. With only 2.9% entering the study with a high tau burden, almost all the others fell in the medium stratification.
Due to the potential for a lower therapeutic response, “patients with low Tau are often excluded from trials,” Dr. Irizarry said. But the sizable proportion of low tau patients has permitted an assessment of relative response with lecanemab, which turned out to be substantial.
“Consistent rates of clinical stability or improvements were observed regardless of baseline tau levels with the highest rates of improvements observed for the low tau group after 24 months of follow-up,” Dr. Irizarry reported.
In previously reported results from the tau PET substudy, lecanemab was shown to slow tau spread at least numerically in every section of the brain evaluated, including the frontal, cingulate, parietal, and whole cortical gray matter areas. The reductions reached significance for the medial temporal (P = .0024), meta temporal (P = .012), and temporal (P = .16) portions.
When most recently evaluated in the OLE, the CDR-SB score declined 38% less among those treated with lecanemab than those treated with placebo in the subgroup enrolled in the tau PET substudy.
Relative to those with intermediate or high tau, patients in the low tau had an even greater reduction in cognitive decline than those with higher tau burdens. Although Dr. Irizarry cautioned that greater baseline CDR-SB scores exaggerated the treatment effect in the low tau group, the message is that “a lecanemab treatment effect is seen even when baseline tau levels are low.”
Now, with the recent market withdrawal of aducanumab, another anti-amyloid monoclonal antibody that was previously approved for Alzheimer’s disease, lecanemab is the only therapy currently available for the goal of changing disease progression, not just modifying symptoms.
Looking Long Term
Both sets of data provide important messages for clinicians, according to Marcelo Matiello, MD, a physician investigator at Mass General Hospital and associate professor of neurology at Harvard Medical School, Boston.
“Clinicians are really looking for more data because this remains a relatively new drug,” he said. Both sets of findings presented by Dr. Irizarry “look good but the follow-up is still short, so I think everyone is still looking closely at long-term safety and efficacy.”
The need for continuous indefinite therapy is one concern that Dr. Matiello expressed. As moderator of the session in which these data were presented, Dr. Matiello specifically asked Dr. Irizarry if there are plans to explore whether periods without treatment might be a means to reduce the cost and burden of frequent infusions while preserving cognitive gains.
In response, Dr. Irizarry said that earlier studies showed rapid progression when lecanemab was stopped. On this basis, he thinks therapy must be maintained, but he did say that there are plans to look at less frequent dosing, such as once per month. He also said that a subcutaneous formulation in development might also reduce the burden of prolonged treatment.
Dr. Irizarry is an employee of Eisai Ltd., which manufacturers lecanemab. Dr. Matiello reports no potential conflicts of interest.
DENVER — , according to a first report of 6-month OLE data.
Due to the steady disease progression observed after the switch of placebo to active therapy, the message of these data is that “early initiation of lecanemab is important,” according to Michael Irizarry, MD, the senior vice president of clinical research at Eisai Ltd, which markets lecanemab.
The 6-month OLE data along with data from a tau PET substudy were presented by Dr. Irizarry at the 2024 annual meeting of the American Academy of Neurology.
From the start of the OLE through the 6-month follow-up, the downward trajectory of cognitive function, as measured with the Clinical Dementia Rating – Sum of Boxes (CDR-SB), has been parallel for the lecanemab-start and switch arms. As a result, the degree of separation between active and placebo groups over the course of the OLE has remained unchanged from the end of the randomized trial.
This does not rule out any benefit in the switch arm, according to Dr. Irizarry. Although there was no discernible change in the trajectory of decline among placebo patients after they were switched to lecanemab, Dr. Irizarry postulated that this might overlook the greater likely decline over time with no treatment.
“There was no placebo group in the OLE to compare with those on active treatment,” he pointed out. He then juxtaposed data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Over the same 6-month timeframe, these data show a hypothetical separation of the curves if no treatment had been received.
The 6-month OLE data provide a preliminary look at outcomes in a planned 4-year follow-up. At the end of the randomized CLARITY trial, the mean decline from the baseline CDR-SB score of 3.2, was 1.21 in the lecanemab group, translating into a 38% decline, and 1.66 in the placebo group, translating into about a 50% decline. Over the 6 months of OLE, there has been a further mean CDR-SB reduction of approximately 0.6 in both arms, suggesting a further 18% decline from baseline.
Additional Data
In the pivotal CLARITY trial, which was published a few months prior to regulatory approval early last year, 1785 patients were randomized to 10 mg/kg lecanemab or placebo infused every 2 weeks. At the end of 18 months, the superiority of lecanemab for the primary endpoint of adverse change in CDR-SB was highly significant (P < .001) as were the differences in key secondary endpoints, such as Alzheimer’s Disease Composite Score (P < .001).
Of those who participated in CLARITY, 1385 patients entered the OLE. Placebo patients were switched to lecanemab which is being maintained in all patients on the trial schedule of 10 mg/kg administered by intravenous infusion every 2 weeks.
In addition to the overall OLE 6-month data, which has not raised any new safety signals, Dr. Irizarry provided a new look at the PET TAU substudy with a focus on patients who entered the study with a low relative tau burden. Of the three classifications, which also included medium and high tau, as measured with positron-emission tomography (PET), the low tau group represented 41.2% of the 342 tau PET substudy participants. With only 2.9% entering the study with a high tau burden, almost all the others fell in the medium stratification.
Due to the potential for a lower therapeutic response, “patients with low Tau are often excluded from trials,” Dr. Irizarry said. But the sizable proportion of low tau patients has permitted an assessment of relative response with lecanemab, which turned out to be substantial.
“Consistent rates of clinical stability or improvements were observed regardless of baseline tau levels with the highest rates of improvements observed for the low tau group after 24 months of follow-up,” Dr. Irizarry reported.
In previously reported results from the tau PET substudy, lecanemab was shown to slow tau spread at least numerically in every section of the brain evaluated, including the frontal, cingulate, parietal, and whole cortical gray matter areas. The reductions reached significance for the medial temporal (P = .0024), meta temporal (P = .012), and temporal (P = .16) portions.
When most recently evaluated in the OLE, the CDR-SB score declined 38% less among those treated with lecanemab than those treated with placebo in the subgroup enrolled in the tau PET substudy.
Relative to those with intermediate or high tau, patients in the low tau had an even greater reduction in cognitive decline than those with higher tau burdens. Although Dr. Irizarry cautioned that greater baseline CDR-SB scores exaggerated the treatment effect in the low tau group, the message is that “a lecanemab treatment effect is seen even when baseline tau levels are low.”
Now, with the recent market withdrawal of aducanumab, another anti-amyloid monoclonal antibody that was previously approved for Alzheimer’s disease, lecanemab is the only therapy currently available for the goal of changing disease progression, not just modifying symptoms.
Looking Long Term
Both sets of data provide important messages for clinicians, according to Marcelo Matiello, MD, a physician investigator at Mass General Hospital and associate professor of neurology at Harvard Medical School, Boston.
“Clinicians are really looking for more data because this remains a relatively new drug,” he said. Both sets of findings presented by Dr. Irizarry “look good but the follow-up is still short, so I think everyone is still looking closely at long-term safety and efficacy.”
The need for continuous indefinite therapy is one concern that Dr. Matiello expressed. As moderator of the session in which these data were presented, Dr. Matiello specifically asked Dr. Irizarry if there are plans to explore whether periods without treatment might be a means to reduce the cost and burden of frequent infusions while preserving cognitive gains.
In response, Dr. Irizarry said that earlier studies showed rapid progression when lecanemab was stopped. On this basis, he thinks therapy must be maintained, but he did say that there are plans to look at less frequent dosing, such as once per month. He also said that a subcutaneous formulation in development might also reduce the burden of prolonged treatment.
Dr. Irizarry is an employee of Eisai Ltd., which manufacturers lecanemab. Dr. Matiello reports no potential conflicts of interest.
FROM AAN 2024