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Neurological Disorders Now Top Global Cause of Illness, Disability
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
FROM THE LANCET NEUROLOGY
Promising Results for Investigational Myasthenia Gravis Drug
, data from a new phase 3 study showed.
After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.
The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.
“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.
The findings were published online in JAMA Neurology.
Unmet Need
A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.
The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.
Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.
“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.
Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.
The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.
The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.
All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
Bests Placebo
Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.
Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.
Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).
While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.
In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.
In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).
Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).
Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.
Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
Well Tolerated
On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.
The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).
“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.
Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.
High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.
The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.
In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.
The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.
The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
Questions Remain
Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.
It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.
The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.
“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.
The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.
A version of this article first appeared on Medscape.com.
, data from a new phase 3 study showed.
After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.
The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.
“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.
The findings were published online in JAMA Neurology.
Unmet Need
A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.
The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.
Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.
“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.
Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.
The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.
The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.
All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
Bests Placebo
Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.
Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.
Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).
While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.
In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.
In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).
Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).
Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.
Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
Well Tolerated
On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.
The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).
“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.
Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.
High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.
The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.
In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.
The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.
The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
Questions Remain
Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.
It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.
The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.
“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.
The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.
A version of this article first appeared on Medscape.com.
, data from a new phase 3 study showed.
After 6 weeks of treatment, patients reported nearly 60% sustained improvement in daily activities and a rapid onset of action from batoclimab, a neonatal crystallizable fragment receptor (FcRn) antagonist.
The clinical effects and the extent of immunoglobulin G (IgG) reduction in this study were similar to those previously reported for efgartigimod and rozanolixizumab, two other FcRn antagonists, the investigators noted, adding that larger studies are needed to better understand the safety profile of batoclimab.
“While most generalized myasthenia gravis patients can achieve good disease control through conventional immunotherapy, there are still unmet needs with this disease,” said study investigator Chongbo Zhao, MD, National Center for Neurological Disorders, Huashan Rare Disease Centre, Department of Neurology, Huashan Hospital of Fudan University, Shanghai, China.
The findings were published online in JAMA Neurology.
Unmet Need
A rare chronic disease, myasthenia gravis is caused by autoantibodies that disrupt the neuromuscular junction, most commonly against the nicotinic acetylcholine receptor (AChR). This can cause a variety of symptoms, including difficulty swallowing, chewing, and talking, as well as severe, sometimes life-threatening, muscle weakness.
The estimated global prevalence of myasthenia gravis is 15-25 per 100,000, with cases doubling in the past 20 years.
Treatment for myasthenia gravis typically includes immune-suppressing drugs. But research suggests almost half of patients with generalized myasthenia gravis don’t achieve an adequate response or are intolerant to these treatments, and some therapies are costly or not readily accessible.
“Our treatment goal has evolved from saving patients to improving their quality of life, so we still need to explore safer and more effective novel treatment methods,” Dr. Zhao said.
Batoclimab is a fully humanized monoclonal IgG antibody that binds to FcRn and accelerates clearance of harmful IgG. A phase 2 trial provided preliminary evidence to support the efficacy of this agent in Chinese patients with generalized myasthenia gravis.
The current double-blind phase 3 trial included 132 adult patients (mean age, 44 years; 67% female) of Chinese Han ethnicity with generalized myasthenia gravis at 27 centers in China. Participants had a mean Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 8.4 at baseline, and all but one was positive for AChR or muscle-specific kinase (MuSK) antibodies.
The treatment group received weekly subcutaneous injections of batoclimab at 680 mg for 6 weeks, followed by 4 weeks of observation. The control group received a placebo with the same treatment and follow-up schedule.
All patients received standard of care in addition to the assigned treatment, but changes in dosage and/or dosing frequency were not permitted. Patients received a second cycle if they still required treatment.
Bests Placebo
Overall, 90% of participants completed all six doses in cycle 1. The second treatment cycle was conducted in 115 patients, with 88% completing all six doses.
Patients were evaluated at baseline and then weekly for MG-ADL, Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite, and the 15-item revised version of the Myasthenia Gravis Quality of Life.
Sustained MG-ADL improvement — the primary outcome — was significantly higher in the batoclimab group compared with placebo (58% vs 31%, respectively; odds ratio, 3.45; P = .001).
While the rate of sustained MG-ADL improvement with batoclimab was lower than that reported for efgartigimod (68%) in a previous trial, that was primarily because of the more stringent definition of sustained MG-ADL improvement (three-point reduction vs two-point reduction from baseline), investigators said.
In the current trial, batoclimab had a rapid onset of action, with scores diverging between the treatment and placebo groups as early as the second week of therapy.
In the second treatment cycle, batoclimab once again outperformed placebo in sustained MG-ADL improvement (63% vs 36%, respectively; P = .002).
Batoclimab also bested placebo on secondary outcomes, including sustained QMG improvement (64% vs 41%; P = .008) and percent of patients achieving minimal symptom expression (25% vs 5%; P = .004).
Results of all subgroup analyses, including by age groups, sex, body weight, body mass index, and MG Foundation of America clinical classification, were consistent with those of the main analysis. The efficacy of batoclimab was also supported by all sensitivity analyses, underscoring the robustness of results.
Batoclimab led to a rapid and sustained reduction in serum AChR antibody levels, with a median reduction of 81% at week 6.
Well Tolerated
On discontinuation of batoclimab, serum total IgG returned to a level comparable with the baseline after 4 weeks. Reversibility of the drug’s effect is important considering the risk for infection from prolonged immune suppression, the authors noted.
The rate of peripheral edema was significantly higher in the treatment than in the placebo groups (39% vs 5%), but all cases were mild or moderate and deemed not clinically significant. The treatment group also had higher rates of upper respiratory tract infections (36% vs 22%) and of urinary tract infections (19% vs 15%).
“Although the incidence of upper respiratory tract and urinary tract infections was higher in the batoclimab group numerically, these were mild infections that did not require special treatment, so this is not a concern,” said Dr. Zhao.
Plasma albumin levels in the batoclimab group decreased significantly throughout the treatment cycle, starting at week 1 and reaching a decline of up to 31% at week 6. These levels increased rapidly toward baseline after treatment discontinuation.
High cholesterol levels were noted in the batoclimab group, plateauing by week 6. But levels returned to near baseline levels within 4 weeks after the final dose, and there were no serious related adverse reactions.
The rate of headache was slightly higher in the treatment group (6% vs 5% for placebo). “This finding may seem minor but could potentially translate into improved adherence in daily practice settings,” the authors wrote.
In previous studies, the efficacy of FcRn inhibitors in the Asian population was only examined in subgroup analyses with limited subjects. Finding an effective FcRn antagonist for China and surrounding regions is particularly important “considering the high mortality rate in hospitalized generalized myasthenia gravis patients in China,” the researchers noted.
The trial included only two treatment cycles, although results of an open-label extension trial examining longer-term efficacy of batoclimab should be available by the end of this year, said Dr. Zhao.
The trial was also not designed to investigate long-term safety, particularly infections and cardiovascular events. Only one study subject was negative for AChR or MuSK antibodies, which prevented researchers from assessing the drug’s efficacy in this subpopulation.
Questions Remain
Commenting on the study, Fredrik Piehl, MD, PhD, professor of neurology, Karolinska Institute, Stockholm, Sweden , said that recent studies of the two other FcRn antagonists were short-term and had limited long-term data. “We don’t know how valuable they may be for continued treatment,” Dr. Piehl said.
It’s also unclear how this new treatment modality compares with existing and emerging drug strategies in terms of the long-term benefit-risk balance, he added.
The rate of adverse events with batoclimab was high compared with placebo in this study and higher than in earlier studies of efgartigimod, Dr. Piehl noted.
“In this study, almost twice as many reported adverse events in the active arm compared with controls, while these differences tended to be smaller in previously reported trials,” he said.
The trial was funded by Nona Biosciences (Suzhou). Dr. Zhao reported being a full-time employee of Nona Biosciences (Suzhou), a subsidiary of Harbour BioMed Inc. He also reported receiving advisory board/consultant fees from Nona Biosciences, Roche, Sanofi, and Zailab outside the submitted work. Dr. Piehl has received research grants from Janssen, Merck KGaA, and UCB; and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche; and preparation of expert witness statement for Novartis.
A version of this article first appeared on Medscape.com.
FROM JAMA NEUROLOGY
Service Dogs Lead to Fewer Seizures in Treatment-Resistant Epilepsy
, a new study showed.
Investigators speculate that the dogs may ease participants’ stress, leading to a decrease in seizure frequency, although they note this relationship warrants more study.
“Despite the development of numerous antiseizure medications over the past 15 years, up to 30% of people with epilepsy experience persistent seizures,” study author Valérie van Hezik-Wester, MSc, of Erasmus University Rotterdam, Rotterdam, the Netherlands, said in a press release.
The unpredictable nature of seizures is one of the most disabling aspects of epilepsy, Ms. Hezik-Wester added. Seizure dogs are trained to recognize seizures and respond when they occur.
“The tasks that these dogs perform, along with their companionship, may reduce seizure-related anxiety, also potentially reducing seizures caused by stress, the most common trigger for seizures,” she said.
The findings were published online in Neurology.
Improve Quality of Life
The study included 25 individuals with medically refractory epilepsy who had an average of two or more seizures per week, with seizure characteristics associated with a high risk for injuries or dysfunction. They also had to be able to care for a service dog.
All were observed under usual care, which included antiseizure medications, neurostimulation devices, and other supportive therapies. Participants could then choose to work with a service dog that had completed socialization and obedience training or be assigned a puppy they would train at home.
The median follow-up was 19 months with usual care and 12 months with the intervention. Participants recorded seizure activity in diaries and completed surveys on seizure severity, quality of life, and well-being every 3 months. Daily seizure counts were converted to obtain cumulative seizure frequencies over 28-day periods.
Of the 25 original participants, six discontinued trial participation before the end of follow-up, four of whom left the study due to difficulty with dog care and training.
Participants receiving usual care reported an average of 115 seizures per 28-day period, while those with trained service dogs recorded 73 seizures in the same period, or a 37% difference between groups.
Researchers found that participants had an average of 31% fewer seizures during the past 3 months when they had seizure dogs, with seven participants achieving a 50%-100% reduction in seizures.
The number of seizure-free days increased from an average of 11 days per 28-day period before receiving a service dog to 15 days after working with a dog.
Scores on the EQ-5D-5L, which measures perceived health problems, decreased on average by 2.5% per consecutive 28-day period with the intervention, reflecting an increase in generic health-related quality of life (0.975; 95% CI, 0.954-0.997).
“These findings show that seizure dogs can help people with epilepsy,” said Ms. van Hezik-Wester. “However, we also found that this partnership with seizure dogs might not be the right fit for everyone, as some people discontinued their participation in this program. More research is needed to better understand which people can benefit from working with seizure dogs.”
Enhanced Quality of Life
In an accompanying editorial, Amir Mbonde, MB, and Amy Crepeau, MD, of Mayo Clinic in Phoenix, Arizona, noted the findings add to a growing body of work on the effectiveness of service dogs in reducing seizure frequency.
“In addition to improved seizure control, the EPISODE study demonstrated the benefit of seizure dogs in enhancing the quality of life for patients, a crucial component of comprehensive epilepsy care,” they wrote.
In prior studies, seizure dogs have identified an odor that a person emits before a seizure in up to 97% of people, they noted, adding that this ability “offers immense clinical benefits to people with epilepsy, enhancing their independence, social engagement, employment opportunities, self-confidence, and thus quality of life.”
Study limitations include its small sample size and high attrition rate.
The study was funded by the Netherlands Organization for Health Research and Development and Innovatiefonds Zorgverzekeraars.
A version of this article appeared on Medscape.com.
, a new study showed.
Investigators speculate that the dogs may ease participants’ stress, leading to a decrease in seizure frequency, although they note this relationship warrants more study.
“Despite the development of numerous antiseizure medications over the past 15 years, up to 30% of people with epilepsy experience persistent seizures,” study author Valérie van Hezik-Wester, MSc, of Erasmus University Rotterdam, Rotterdam, the Netherlands, said in a press release.
The unpredictable nature of seizures is one of the most disabling aspects of epilepsy, Ms. Hezik-Wester added. Seizure dogs are trained to recognize seizures and respond when they occur.
“The tasks that these dogs perform, along with their companionship, may reduce seizure-related anxiety, also potentially reducing seizures caused by stress, the most common trigger for seizures,” she said.
The findings were published online in Neurology.
Improve Quality of Life
The study included 25 individuals with medically refractory epilepsy who had an average of two or more seizures per week, with seizure characteristics associated with a high risk for injuries or dysfunction. They also had to be able to care for a service dog.
All were observed under usual care, which included antiseizure medications, neurostimulation devices, and other supportive therapies. Participants could then choose to work with a service dog that had completed socialization and obedience training or be assigned a puppy they would train at home.
The median follow-up was 19 months with usual care and 12 months with the intervention. Participants recorded seizure activity in diaries and completed surveys on seizure severity, quality of life, and well-being every 3 months. Daily seizure counts were converted to obtain cumulative seizure frequencies over 28-day periods.
Of the 25 original participants, six discontinued trial participation before the end of follow-up, four of whom left the study due to difficulty with dog care and training.
Participants receiving usual care reported an average of 115 seizures per 28-day period, while those with trained service dogs recorded 73 seizures in the same period, or a 37% difference between groups.
Researchers found that participants had an average of 31% fewer seizures during the past 3 months when they had seizure dogs, with seven participants achieving a 50%-100% reduction in seizures.
The number of seizure-free days increased from an average of 11 days per 28-day period before receiving a service dog to 15 days after working with a dog.
Scores on the EQ-5D-5L, which measures perceived health problems, decreased on average by 2.5% per consecutive 28-day period with the intervention, reflecting an increase in generic health-related quality of life (0.975; 95% CI, 0.954-0.997).
“These findings show that seizure dogs can help people with epilepsy,” said Ms. van Hezik-Wester. “However, we also found that this partnership with seizure dogs might not be the right fit for everyone, as some people discontinued their participation in this program. More research is needed to better understand which people can benefit from working with seizure dogs.”
Enhanced Quality of Life
In an accompanying editorial, Amir Mbonde, MB, and Amy Crepeau, MD, of Mayo Clinic in Phoenix, Arizona, noted the findings add to a growing body of work on the effectiveness of service dogs in reducing seizure frequency.
“In addition to improved seizure control, the EPISODE study demonstrated the benefit of seizure dogs in enhancing the quality of life for patients, a crucial component of comprehensive epilepsy care,” they wrote.
In prior studies, seizure dogs have identified an odor that a person emits before a seizure in up to 97% of people, they noted, adding that this ability “offers immense clinical benefits to people with epilepsy, enhancing their independence, social engagement, employment opportunities, self-confidence, and thus quality of life.”
Study limitations include its small sample size and high attrition rate.
The study was funded by the Netherlands Organization for Health Research and Development and Innovatiefonds Zorgverzekeraars.
A version of this article appeared on Medscape.com.
, a new study showed.
Investigators speculate that the dogs may ease participants’ stress, leading to a decrease in seizure frequency, although they note this relationship warrants more study.
“Despite the development of numerous antiseizure medications over the past 15 years, up to 30% of people with epilepsy experience persistent seizures,” study author Valérie van Hezik-Wester, MSc, of Erasmus University Rotterdam, Rotterdam, the Netherlands, said in a press release.
The unpredictable nature of seizures is one of the most disabling aspects of epilepsy, Ms. Hezik-Wester added. Seizure dogs are trained to recognize seizures and respond when they occur.
“The tasks that these dogs perform, along with their companionship, may reduce seizure-related anxiety, also potentially reducing seizures caused by stress, the most common trigger for seizures,” she said.
The findings were published online in Neurology.
Improve Quality of Life
The study included 25 individuals with medically refractory epilepsy who had an average of two or more seizures per week, with seizure characteristics associated with a high risk for injuries or dysfunction. They also had to be able to care for a service dog.
All were observed under usual care, which included antiseizure medications, neurostimulation devices, and other supportive therapies. Participants could then choose to work with a service dog that had completed socialization and obedience training or be assigned a puppy they would train at home.
The median follow-up was 19 months with usual care and 12 months with the intervention. Participants recorded seizure activity in diaries and completed surveys on seizure severity, quality of life, and well-being every 3 months. Daily seizure counts were converted to obtain cumulative seizure frequencies over 28-day periods.
Of the 25 original participants, six discontinued trial participation before the end of follow-up, four of whom left the study due to difficulty with dog care and training.
Participants receiving usual care reported an average of 115 seizures per 28-day period, while those with trained service dogs recorded 73 seizures in the same period, or a 37% difference between groups.
Researchers found that participants had an average of 31% fewer seizures during the past 3 months when they had seizure dogs, with seven participants achieving a 50%-100% reduction in seizures.
The number of seizure-free days increased from an average of 11 days per 28-day period before receiving a service dog to 15 days after working with a dog.
Scores on the EQ-5D-5L, which measures perceived health problems, decreased on average by 2.5% per consecutive 28-day period with the intervention, reflecting an increase in generic health-related quality of life (0.975; 95% CI, 0.954-0.997).
“These findings show that seizure dogs can help people with epilepsy,” said Ms. van Hezik-Wester. “However, we also found that this partnership with seizure dogs might not be the right fit for everyone, as some people discontinued their participation in this program. More research is needed to better understand which people can benefit from working with seizure dogs.”
Enhanced Quality of Life
In an accompanying editorial, Amir Mbonde, MB, and Amy Crepeau, MD, of Mayo Clinic in Phoenix, Arizona, noted the findings add to a growing body of work on the effectiveness of service dogs in reducing seizure frequency.
“In addition to improved seizure control, the EPISODE study demonstrated the benefit of seizure dogs in enhancing the quality of life for patients, a crucial component of comprehensive epilepsy care,” they wrote.
In prior studies, seizure dogs have identified an odor that a person emits before a seizure in up to 97% of people, they noted, adding that this ability “offers immense clinical benefits to people with epilepsy, enhancing their independence, social engagement, employment opportunities, self-confidence, and thus quality of life.”
Study limitations include its small sample size and high attrition rate.
The study was funded by the Netherlands Organization for Health Research and Development and Innovatiefonds Zorgverzekeraars.
A version of this article appeared on Medscape.com.
FROM NEUROLOGY
New Data Support Viagra for Alzheimer’s Prevention
The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.
This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).
“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release.
“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted.
The study was published online in the Journal of Alzheimer’s Disease.
Neuroprotective?
Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities.
They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs.
For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.
The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.
However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.
The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons.
They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.
“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said.
The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures.
A version of this article appeared on Medscape.com.
The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.
This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).
“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release.
“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted.
The study was published online in the Journal of Alzheimer’s Disease.
Neuroprotective?
Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities.
They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs.
For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.
The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.
However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.
The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons.
They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.
“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said.
The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures.
A version of this article appeared on Medscape.com.
The large real-world analysis of patient data from two databases showed a 30%-54% reduced prevalence in Alzheimer’s disease among patients who took sildenafil (Viagra) than those who did not, after adjusting for potential confounding factors.
This observation was further supported by mechanistic studies showing decreased neurotoxic protein levels in brain cells exposed to the phosphodiesterase type 5 inhibitor (PDE5i).
“Our findings provide further weight to repurposing this existing FDA-approved drug as a novel treatment for Alzheimer’s, which is in great need of new therapies,” Feixiong Cheng, PhD, director of the Cleveland Clinic Genome Center, who led the research, said in a news release.
“We used artificial intelligence to integrate data across multiple domains which all indicated sildenafil’s potential against this devastating neurological disease,” Dr. Cheng noted.
The study was published online in the Journal of Alzheimer’s Disease.
Neuroprotective?
Using real-world patient data from the MarketScan Medicare Supplemental database (2012-2017) and the Clinformatics database (2007-2020), the researchers conducted propensity score-stratified analyses after adjusting for gender, age, race, and comorbidities.
They searched for all individuals with pharmacy claims for sildenafil or four comparator drugs — bumetanide, furosemide, spironolactone, and nifedipine. Results showed that sildenafil use was associated with reduced likelihood of Alzheimer’s disease relative to the control drugs.
For example, sildenafil use was associated with a 54% reduced incidence of Alzheimer’s disease in MarketScan (hazard ratio [HR], 0.46; 95% CI, 0.32-0.66) and a 30% reduced prevalence of Alzheimer’s disease in Clinformatics (HR, 0.70; 95% CI, 0.49-1.00) compared with spironolactone.
The findings support a study published earlier this year that found a potential protective effect of PDE5i treatment on Alzheimer’s disease risk.
However, this research and the current study are contradicted by another paper published in Brain Communications in late 2022 which showed no such link between ED meds and reduced Alzheimer’s disease risk.
The investigators also found that sildenafil reduces tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic Alzheimer’s disease patient induced pluripotent stem cell (iPSC)-derived neurons.
They further demonstrated through RNA-sequencing data analysis that sildenafil specifically targets Alzheimer’s disease related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in Alzheimer’s disease.
“We believe our findings provide the evidence needed for clinical trials to further examine the potential effectiveness of sildenafil in patients with Alzheimer’s disease,” Dr. Cheng said.
The study was primarily supported by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cheng had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM THE JOURNAL OF ALZHEIMER’S RESEARCH
Frexalimab Promising for Relapsing Multiple Sclerosis
At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.
The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.
The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
‘Unambiguous Benefit’
Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.
“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.
The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.
Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).
All but four patients completed the 12-week double-blind period and entered the open-label period.
The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.
At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.
The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.
On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.
The effects were sustained over time across both active treatment groups.
Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
Phase 3 Trials Underway
The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.
There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.
No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.
Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.
Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
‘A High Bar for Any New Treatment’
In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”
If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”
Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”
“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”
“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.
While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.
The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article first appeared on Medscape.com.
At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.
The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.
The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
‘Unambiguous Benefit’
Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.
“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.
The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.
Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).
All but four patients completed the 12-week double-blind period and entered the open-label period.
The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.
At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.
The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.
On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.
The effects were sustained over time across both active treatment groups.
Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
Phase 3 Trials Underway
The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.
There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.
No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.
Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.
Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
‘A High Bar for Any New Treatment’
In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”
If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”
Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”
“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”
“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.
While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.
The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article first appeared on Medscape.com.
At week 12, there was an 89% reduction in new gadolinium (Gd)-enhancing T1 brain lesions — a standard measure of active inflammation in MS – in the high-dose frexalimab group and a 79% reduction in the low-dose treatment group compared with placebo, meeting the study’s primary endpoint.
The effects of frexalimab were sustained over time, “especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment,” first author Patrick Vermersch, MD, PhD, University of Lille, CHU Lille, France, said in a news release.
The full results were published online on in The New England Journal of Medicine, following presentation of preliminary data at the Consortium of Multiple Sclerosis Centers 2023 Annual Meeting.
‘Unambiguous Benefit’
Frexalimab blocks the costimulatory CD40/CD40L pathway, which regulates both adaptive and innate immune responses, and has been implicated in the pathogenesis of MS.
“Through this unique upstream mechanism of action, frexalimab has the potential to address both acute and chronic neuroinflammation in MS, without causing lymphocyte depletion,” a Sanofi press statement noted.
The phase 2 study enrolled 129 adults (mean age, 36 years; 66% women) with relapsing MS, 30% of whom had Gd-enhancing lesions at baseline.
Participants received 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose; n = 52), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose; n = 51), or matching placebos for each active treatment (n = 12 and n = 14, respectively).
All but four patients completed the 12-week double-blind period and entered the open-label period.
The primary end point was the number of new Gd-enhancing T1-weighted lesions seen on MRI at week 12 relative to week 8.
At week 12, the adjusted mean number of new Gd-enhancing T1 lesions was 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in the pooled placebo group.
The rate ratios, as compared with placebo, were 0.11 in the high-dose group and 0.21 in the low-dose group, corresponding to 89% and 79% reductions in the high- and low-dose groups, respectively.
On the secondary endpoint of number of new/enlarging T2-weighted lesions at week 12, rate ratios in the high- and low-dose groups were 0.08 and 0.14, respectively, corresponding to 92% and 86% reduction in the high- and low-dose treatment groups vs placebo.
The effects were sustained over time across both active treatment groups.
Frexalimab also lowered plasma levels of neurofilament light chain, a biomarker of neuroaxonal damage in MS, as well as plasma levels of CXCL13, a biomarker of inflammatory activity.
Phase 3 Trials Underway
The authors noted that the trial was too brief and small to draw conclusions regarding clinical outcomes. However, during the 12-week double-blind period, no relapses occurred in the high-dose frexalimab group, whereas relapses occurred in roughly 4% of those in the low-dose frexalimab group and the pooled placebo group.
There was no change from baseline to 12 weeks in median scores on the Expanded Disability Status Scale in any study group.
No serious or severe adverse events or deaths were reported during the double-blind period. There were no thromboembolic events — a concern with first-generation anti–CD40L antibodies.
Depletion of lymphocytes was not observed. More infections were observed with frexalimab than with placebo, but no serious infections occurred during 24 weeks of frexalimab treatment. The most common adverse events were COVID-19 and headache. All cases of COVID-19 were uncomplicated and mild to moderate in severity.
Bolstered by the promising phase 2 data, Sanofi has initiated two phase 3 studies assessing frexalimab in relapsing MS and non-relapsing secondary progressive MS.
‘A High Bar for Any New Treatment’
In an accompanying editorial, Stephen L. Hauser, MD, with UCSF Weill Institute for Neurosciences, San Francisco, California, wrote that the results “appear clear, although the clinical significance is uncertain — clear because there was an unambiguous benefit with regard to short-term MRI outcomes in patients who received frexalimab as compared with those who received placebo and because a generally low level of MRI activity persisted during an additional 12-week open-label extension period.”
If the findings hold with longer-term use, Dr. Hauser continued, “it seems likely that there will be a protective effect of frexalimab therapy with regard to relapses of multiple sclerosis.”
Dr. Hauser noted, however, that the “striking clinical benefits and safety profile of the available high-efficacy therapies for relapsing multiple sclerosis create a high bar for any new treatment.”
“In this trial, the MRI outcomes with frexalimab therapy were impressive but appear to be less complete than those with anti-CD20 agents, although trials of different agents cannot be directly compared.”
“Even if future studies show frexalimab to be competitive with currently available therapies for relapsing multiple sclerosis, the paramount need is for more effective therapy against progression,” Dr. Hauser wrote.
While the current trial was neither designed nor powered to assess benefits against progressive MS, “progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined,” Dr. Hauser concluded.
The study was supported by Sanofi. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Seizure Risk Is Nearly Double in Patients With MS
TOPLINE:
, results of a new meta-analysis of randomized controlled trials (RCTs) suggest. Those with a progressive disease phenotype are at particularly high seizure risk.
METHODOLOGY:
- The meta-analysis included 63 phase 3 RCTs with 53,535 patients.
- Most of the studies included in the meta-analysis investigated disease-modifying treatments compared with placebo or an active comparator such as interferon beta, teriflunomide, and dimethyl fumarate, in terms of relapse rate and/or disability progression.
- Researchers extracted relevant information from studies, including MS subtype (clinically isolated syndrome, relapsing-remitting, primary progressive, or secondary progressive MS), mean Expanded Disability Status Scale (EDSS) score, lesion volume on T2-hyperintense sequence, normalized brain volume, and number of seizures or epilepsy events.
- They calculated the pooled effect size of studies on the incidence rate of seizure or epilepsy as the number of events per patient-years and explored which variables influenced the pooled effect size.
TAKEAWAY:
- A total of 120 patients experienced epileptic seizure events over a median follow-up of 2 years, resulting in a pooled incidence rate of 68.0 (95% CI, 49.1-86.9) per 100,000 patient-years, which investigators noted is significantly higher than the general population rate of 34.6.
- Higher seizure incidence rates were found among patients with progressive disease courses, longer time since clinical onset, higher EDSS scores, and lower normalized brain volume; age and T2 lesion volume did not affect the pooled effect size.
- Patients treated with S1PR modulators (fingolimod, ozanimod, ponesimod, and siponimod) had more than double the risk for seizure compared with placebo or comparators (estimated incident seizure risk ratio, 2.45; P = .008).
IN PRACTICE:
“Our findings underscore epilepsy as a significant comorbidity in MS and emphasize the necessity for further research into its triggers, preventive measures and treatment strategies,” the authors wrote.
SOURCE:
The study, led by Valeria Pozzilli, Unit of Neurology, Neurophysiology and Neurobiology, Department of Medicine and Surgery, Campus Bio-Medico University, Roma, Italy, was published online in the Journal of Neurology, Neurosurgery, and Psychiatry.
LIMITATIONS:
As none of the included RCTs considered epilepsy an exclusion criterion, patients with comorbid epilepsy may have been enrolled in these studies. There was significant diversity in reporting of adverse events across studies. While this study’s statistical methodology was robust, the findings can’t be applied directly to individuals due to the risk for ecological fallacy.
DISCLOSURES:
Pozzilli had no relevant conflicts of interests. See paper for disclosures of other authors.
A version of this article appeared on Medscape.com.
TOPLINE:
, results of a new meta-analysis of randomized controlled trials (RCTs) suggest. Those with a progressive disease phenotype are at particularly high seizure risk.
METHODOLOGY:
- The meta-analysis included 63 phase 3 RCTs with 53,535 patients.
- Most of the studies included in the meta-analysis investigated disease-modifying treatments compared with placebo or an active comparator such as interferon beta, teriflunomide, and dimethyl fumarate, in terms of relapse rate and/or disability progression.
- Researchers extracted relevant information from studies, including MS subtype (clinically isolated syndrome, relapsing-remitting, primary progressive, or secondary progressive MS), mean Expanded Disability Status Scale (EDSS) score, lesion volume on T2-hyperintense sequence, normalized brain volume, and number of seizures or epilepsy events.
- They calculated the pooled effect size of studies on the incidence rate of seizure or epilepsy as the number of events per patient-years and explored which variables influenced the pooled effect size.
TAKEAWAY:
- A total of 120 patients experienced epileptic seizure events over a median follow-up of 2 years, resulting in a pooled incidence rate of 68.0 (95% CI, 49.1-86.9) per 100,000 patient-years, which investigators noted is significantly higher than the general population rate of 34.6.
- Higher seizure incidence rates were found among patients with progressive disease courses, longer time since clinical onset, higher EDSS scores, and lower normalized brain volume; age and T2 lesion volume did not affect the pooled effect size.
- Patients treated with S1PR modulators (fingolimod, ozanimod, ponesimod, and siponimod) had more than double the risk for seizure compared with placebo or comparators (estimated incident seizure risk ratio, 2.45; P = .008).
IN PRACTICE:
“Our findings underscore epilepsy as a significant comorbidity in MS and emphasize the necessity for further research into its triggers, preventive measures and treatment strategies,” the authors wrote.
SOURCE:
The study, led by Valeria Pozzilli, Unit of Neurology, Neurophysiology and Neurobiology, Department of Medicine and Surgery, Campus Bio-Medico University, Roma, Italy, was published online in the Journal of Neurology, Neurosurgery, and Psychiatry.
LIMITATIONS:
As none of the included RCTs considered epilepsy an exclusion criterion, patients with comorbid epilepsy may have been enrolled in these studies. There was significant diversity in reporting of adverse events across studies. While this study’s statistical methodology was robust, the findings can’t be applied directly to individuals due to the risk for ecological fallacy.
DISCLOSURES:
Pozzilli had no relevant conflicts of interests. See paper for disclosures of other authors.
A version of this article appeared on Medscape.com.
TOPLINE:
, results of a new meta-analysis of randomized controlled trials (RCTs) suggest. Those with a progressive disease phenotype are at particularly high seizure risk.
METHODOLOGY:
- The meta-analysis included 63 phase 3 RCTs with 53,535 patients.
- Most of the studies included in the meta-analysis investigated disease-modifying treatments compared with placebo or an active comparator such as interferon beta, teriflunomide, and dimethyl fumarate, in terms of relapse rate and/or disability progression.
- Researchers extracted relevant information from studies, including MS subtype (clinically isolated syndrome, relapsing-remitting, primary progressive, or secondary progressive MS), mean Expanded Disability Status Scale (EDSS) score, lesion volume on T2-hyperintense sequence, normalized brain volume, and number of seizures or epilepsy events.
- They calculated the pooled effect size of studies on the incidence rate of seizure or epilepsy as the number of events per patient-years and explored which variables influenced the pooled effect size.
TAKEAWAY:
- A total of 120 patients experienced epileptic seizure events over a median follow-up of 2 years, resulting in a pooled incidence rate of 68.0 (95% CI, 49.1-86.9) per 100,000 patient-years, which investigators noted is significantly higher than the general population rate of 34.6.
- Higher seizure incidence rates were found among patients with progressive disease courses, longer time since clinical onset, higher EDSS scores, and lower normalized brain volume; age and T2 lesion volume did not affect the pooled effect size.
- Patients treated with S1PR modulators (fingolimod, ozanimod, ponesimod, and siponimod) had more than double the risk for seizure compared with placebo or comparators (estimated incident seizure risk ratio, 2.45; P = .008).
IN PRACTICE:
“Our findings underscore epilepsy as a significant comorbidity in MS and emphasize the necessity for further research into its triggers, preventive measures and treatment strategies,” the authors wrote.
SOURCE:
The study, led by Valeria Pozzilli, Unit of Neurology, Neurophysiology and Neurobiology, Department of Medicine and Surgery, Campus Bio-Medico University, Roma, Italy, was published online in the Journal of Neurology, Neurosurgery, and Psychiatry.
LIMITATIONS:
As none of the included RCTs considered epilepsy an exclusion criterion, patients with comorbid epilepsy may have been enrolled in these studies. There was significant diversity in reporting of adverse events across studies. While this study’s statistical methodology was robust, the findings can’t be applied directly to individuals due to the risk for ecological fallacy.
DISCLOSURES:
Pozzilli had no relevant conflicts of interests. See paper for disclosures of other authors.
A version of this article appeared on Medscape.com.
‘Remarkable’ Study Tracks Timeline of Biomarker Changes 20 Years Before Alzheimer’s disease
, something that hasn’t previously been extensively investigated in longitudinal studies.
By analyzing cerebral spinal fluid (CSF), as well as cognitive and brain imaging assessments conducted every few years for two decades, researchers were able to plot the course of changing levels of amyloid-beta 42 (Abeta42), phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL) in adults with Alzheimer’s disease and mark when those levels began to deviate from those of adults without Alzheimer’s disease.
Levels of Abeta42 in CSF and the ratio of Abeta42 to Abeta40 in people who developed Alzheimer’s disease diverged from those of peers who remained cognitively normal at 18 years and 14 years, respectively, before clinical signs of disease appeared.
The level of p-tau181 in CSF increased 11 years before disease onset, and NfL levels, a measure of neurodegeneration, increased 9 years before diagnosis.
These changes were followed by hippocampal atrophy and cognitive decline a few years later.
The results also show “an apparent accelerated change in concentrations of CSF biomarkers followed by a slowing of this change up to the time of diagnosis,” report the authors, led by Jianping Jia, MD, PhD, with the Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.
The study was published online in The New England Journal of Medicine.
Time Course of Biomarker Changes
Dr. Jia and colleagues conducted a nested case-control study within the China Cognition and Aging Study (COAST). They matched 648 adults who developed Alzheimer’s disease to 648 who remained cognitively normal. CSF, cognitive, and brain imaging assessments were performed every 2-3 years for a median of about 20 years.
Within both groups, men slightly outnumbered women. At baseline, CSF biomarker levels, cognitive scores, and hippocampal volumes were similar in the two groups. Adults who developed Alzheimer’s disease were more likely than their matched controls to be carriers of the APOE epsilon-4 allele (37% vs 20%).
In terms of CSF Abeta42, the level of this biomarker in those who developed Alzheimer’s disease diverged from the level in controls an estimated 18 years before clinical diagnosis. At that time, the level was lower by a mean 59.13 pg/mL in the Alzheimer’s disease group.
A difference in the ratio of CSF Abeta42 to Abeta40 between the two groups appeared an estimated 14 years before the diagnosis of Alzheimer’s disease (difference in mean values, −0.01 pg/mL).
Differences between the two groups in CSF p-tau181 and total tau concentrations were apparent roughly 11 and 10 years before diagnosis, respectively. At those times, the mean differences in p-tau181 and total tau concentrations were 7.10 pg/mL and 87.10 pg/mL, respectively.
In terms of NfL, a difference between the groups was observed 9 years before diagnosis, with its trajectory progressively deviating from the concentrations observed in cognitively normal groups at that time, to a final mean difference in NfL of 228.29 pg/mL.
Bilateral hippocampal volume decreased with age in both groups. However, the decrease began to differ between the two groups 8 years before Alzheimer’s disease diagnosis, at which time volume was lower by 358.94 mm3 in the Alzheimer’s disease group compared with the control group.
Average Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores in the Alzheimer’s disease group began to worsen compared with the control group at about 6 years before diagnosis.
As Alzheimer’s disease progressed, changes in CSF biomarkers increased before reaching a plateau.
Important Contribution
In a linked editorial, Richard Mayeux, MD, Department of Neurology, Columbia University, New York, said the importance of this work “cannot be overstated. Knowledge of the timing of these physiological events is critical to provide clinicians with useful starting points for prevention and therapeutic strategies.”
Dr. Mayeux said this “remarkable” longitudinal study spanning 2 decades “not only confirms the hypotheses of previous investigators but extends and validates the sequence of changes” in sporadic Alzheimer’s disease.
Dr. Mayeux acknowledged that one might consider the finding in this study to be limited owing to the inclusion of only individuals of Han Chinese ancestry.
However, longitudinal studies of plasma biomarkers in individuals of Asian, European, African, and Hispanic ancestry have shown similar trends in biomarker changes preceding the onset of Alzheimer’s disease, he noted.
“Ethnic variation in these biomarkers is known, but that fact does not lessen the effect of the results reported. It merely highlights that similar studies must continue and must be inclusive of other groups,” Dr. Mayeux concluded.
The study had no commercial funding. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article appeared on Medscape.com.
, something that hasn’t previously been extensively investigated in longitudinal studies.
By analyzing cerebral spinal fluid (CSF), as well as cognitive and brain imaging assessments conducted every few years for two decades, researchers were able to plot the course of changing levels of amyloid-beta 42 (Abeta42), phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL) in adults with Alzheimer’s disease and mark when those levels began to deviate from those of adults without Alzheimer’s disease.
Levels of Abeta42 in CSF and the ratio of Abeta42 to Abeta40 in people who developed Alzheimer’s disease diverged from those of peers who remained cognitively normal at 18 years and 14 years, respectively, before clinical signs of disease appeared.
The level of p-tau181 in CSF increased 11 years before disease onset, and NfL levels, a measure of neurodegeneration, increased 9 years before diagnosis.
These changes were followed by hippocampal atrophy and cognitive decline a few years later.
The results also show “an apparent accelerated change in concentrations of CSF biomarkers followed by a slowing of this change up to the time of diagnosis,” report the authors, led by Jianping Jia, MD, PhD, with the Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.
The study was published online in The New England Journal of Medicine.
Time Course of Biomarker Changes
Dr. Jia and colleagues conducted a nested case-control study within the China Cognition and Aging Study (COAST). They matched 648 adults who developed Alzheimer’s disease to 648 who remained cognitively normal. CSF, cognitive, and brain imaging assessments were performed every 2-3 years for a median of about 20 years.
Within both groups, men slightly outnumbered women. At baseline, CSF biomarker levels, cognitive scores, and hippocampal volumes were similar in the two groups. Adults who developed Alzheimer’s disease were more likely than their matched controls to be carriers of the APOE epsilon-4 allele (37% vs 20%).
In terms of CSF Abeta42, the level of this biomarker in those who developed Alzheimer’s disease diverged from the level in controls an estimated 18 years before clinical diagnosis. At that time, the level was lower by a mean 59.13 pg/mL in the Alzheimer’s disease group.
A difference in the ratio of CSF Abeta42 to Abeta40 between the two groups appeared an estimated 14 years before the diagnosis of Alzheimer’s disease (difference in mean values, −0.01 pg/mL).
Differences between the two groups in CSF p-tau181 and total tau concentrations were apparent roughly 11 and 10 years before diagnosis, respectively. At those times, the mean differences in p-tau181 and total tau concentrations were 7.10 pg/mL and 87.10 pg/mL, respectively.
In terms of NfL, a difference between the groups was observed 9 years before diagnosis, with its trajectory progressively deviating from the concentrations observed in cognitively normal groups at that time, to a final mean difference in NfL of 228.29 pg/mL.
Bilateral hippocampal volume decreased with age in both groups. However, the decrease began to differ between the two groups 8 years before Alzheimer’s disease diagnosis, at which time volume was lower by 358.94 mm3 in the Alzheimer’s disease group compared with the control group.
Average Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores in the Alzheimer’s disease group began to worsen compared with the control group at about 6 years before diagnosis.
As Alzheimer’s disease progressed, changes in CSF biomarkers increased before reaching a plateau.
Important Contribution
In a linked editorial, Richard Mayeux, MD, Department of Neurology, Columbia University, New York, said the importance of this work “cannot be overstated. Knowledge of the timing of these physiological events is critical to provide clinicians with useful starting points for prevention and therapeutic strategies.”
Dr. Mayeux said this “remarkable” longitudinal study spanning 2 decades “not only confirms the hypotheses of previous investigators but extends and validates the sequence of changes” in sporadic Alzheimer’s disease.
Dr. Mayeux acknowledged that one might consider the finding in this study to be limited owing to the inclusion of only individuals of Han Chinese ancestry.
However, longitudinal studies of plasma biomarkers in individuals of Asian, European, African, and Hispanic ancestry have shown similar trends in biomarker changes preceding the onset of Alzheimer’s disease, he noted.
“Ethnic variation in these biomarkers is known, but that fact does not lessen the effect of the results reported. It merely highlights that similar studies must continue and must be inclusive of other groups,” Dr. Mayeux concluded.
The study had no commercial funding. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article appeared on Medscape.com.
, something that hasn’t previously been extensively investigated in longitudinal studies.
By analyzing cerebral spinal fluid (CSF), as well as cognitive and brain imaging assessments conducted every few years for two decades, researchers were able to plot the course of changing levels of amyloid-beta 42 (Abeta42), phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL) in adults with Alzheimer’s disease and mark when those levels began to deviate from those of adults without Alzheimer’s disease.
Levels of Abeta42 in CSF and the ratio of Abeta42 to Abeta40 in people who developed Alzheimer’s disease diverged from those of peers who remained cognitively normal at 18 years and 14 years, respectively, before clinical signs of disease appeared.
The level of p-tau181 in CSF increased 11 years before disease onset, and NfL levels, a measure of neurodegeneration, increased 9 years before diagnosis.
These changes were followed by hippocampal atrophy and cognitive decline a few years later.
The results also show “an apparent accelerated change in concentrations of CSF biomarkers followed by a slowing of this change up to the time of diagnosis,” report the authors, led by Jianping Jia, MD, PhD, with the Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China.
The study was published online in The New England Journal of Medicine.
Time Course of Biomarker Changes
Dr. Jia and colleagues conducted a nested case-control study within the China Cognition and Aging Study (COAST). They matched 648 adults who developed Alzheimer’s disease to 648 who remained cognitively normal. CSF, cognitive, and brain imaging assessments were performed every 2-3 years for a median of about 20 years.
Within both groups, men slightly outnumbered women. At baseline, CSF biomarker levels, cognitive scores, and hippocampal volumes were similar in the two groups. Adults who developed Alzheimer’s disease were more likely than their matched controls to be carriers of the APOE epsilon-4 allele (37% vs 20%).
In terms of CSF Abeta42, the level of this biomarker in those who developed Alzheimer’s disease diverged from the level in controls an estimated 18 years before clinical diagnosis. At that time, the level was lower by a mean 59.13 pg/mL in the Alzheimer’s disease group.
A difference in the ratio of CSF Abeta42 to Abeta40 between the two groups appeared an estimated 14 years before the diagnosis of Alzheimer’s disease (difference in mean values, −0.01 pg/mL).
Differences between the two groups in CSF p-tau181 and total tau concentrations were apparent roughly 11 and 10 years before diagnosis, respectively. At those times, the mean differences in p-tau181 and total tau concentrations were 7.10 pg/mL and 87.10 pg/mL, respectively.
In terms of NfL, a difference between the groups was observed 9 years before diagnosis, with its trajectory progressively deviating from the concentrations observed in cognitively normal groups at that time, to a final mean difference in NfL of 228.29 pg/mL.
Bilateral hippocampal volume decreased with age in both groups. However, the decrease began to differ between the two groups 8 years before Alzheimer’s disease diagnosis, at which time volume was lower by 358.94 mm3 in the Alzheimer’s disease group compared with the control group.
Average Clinical Dementia Rating–Sum of Boxes (CDR-SB) scores in the Alzheimer’s disease group began to worsen compared with the control group at about 6 years before diagnosis.
As Alzheimer’s disease progressed, changes in CSF biomarkers increased before reaching a plateau.
Important Contribution
In a linked editorial, Richard Mayeux, MD, Department of Neurology, Columbia University, New York, said the importance of this work “cannot be overstated. Knowledge of the timing of these physiological events is critical to provide clinicians with useful starting points for prevention and therapeutic strategies.”
Dr. Mayeux said this “remarkable” longitudinal study spanning 2 decades “not only confirms the hypotheses of previous investigators but extends and validates the sequence of changes” in sporadic Alzheimer’s disease.
Dr. Mayeux acknowledged that one might consider the finding in this study to be limited owing to the inclusion of only individuals of Han Chinese ancestry.
However, longitudinal studies of plasma biomarkers in individuals of Asian, European, African, and Hispanic ancestry have shown similar trends in biomarker changes preceding the onset of Alzheimer’s disease, he noted.
“Ethnic variation in these biomarkers is known, but that fact does not lessen the effect of the results reported. It merely highlights that similar studies must continue and must be inclusive of other groups,” Dr. Mayeux concluded.
The study had no commercial funding. Disclosures for authors and editorialist are available at NEJM.org.
A version of this article appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
5 Interesting Neurology Studies
This transcript has been edited for clarity.
Dear colleagues, I’m Christoph Diener from the medical faculty of University Duisburg-Essen in Germany. Today I would like to tell you about five interesting studies that were published in January 2024.
Long COVID
I would like to start with long COVID. There is an ongoing discussion about whether this condition — which means symptoms like dizziness, vertigo, fatigue, headache, and cognitive impairment that persist for more than 6 months — is either a consequence of the infection, functional symptoms, psychosomatic disease, or a depression.
There is an important paper that came out in Science. The group investigated 39 controls and 113 patients who had COVID-19. At 6 months, 40 of them had long COVID. The researchers repeatedly measured more than 6500 proteins in serum. The patients with long COVID had a significant increase in complement activation, which persisted even beyond 6 months. These patients also showed increased tissue lesion markers in the blood and activation of the endothelium.
Also, they had increased platelet activation and autoantibodies with increased anti-cytomegalovirus and anti-Epstein-Barr virus immunoglobulins. These are very strong indicators that COVID-19 leads to long-term changes in our immune system, and different activations of complement factors could explain the variety of symptoms that these patients display. Whether this has consequences for treatment is unclear at the moment.
Parkinson’s Classification
Let me come to another issue, which is the future treatment of Parkinson’s disease, covered in a paper in The Lancet Neurology. I think you are all aware that once patients display symptoms like rigidity, bradykinesia, or tremor, it’s most probably too late for neuroprotective therapy because 70% of the dopaminergic neurons are already dead.
The authors propose a new biological diagnosis of the disease in the preclinical state. This early preclinical diagnosis has three components. One is to show the presence of synuclein either in skin biopsy or in serum. The second is proof of neurodegeneration either by MRI or by PET imaging. The third involves genetic markers.
On top of this, we know that we have preclinical manifestations of Parkinson’s disease, like REM sleep disorders, autonomic disturbances, and cognitive impairment. With this new classification, we should be able to identify the preclinical phase of Parkinson’s disease and include these patients in future trials for neuroprotection.
Niemann-Pick Disease
My third study, in The New England Journal of Medicine, deals with Niemann-Pick disease type C (Trial of N-Acetyl-l-Leucine in Niemann–Pick Disease Type C. This is a rare autosomal recessive disorder that involves impaired lysosomal storage. This disease, which manifests usually in childhood, goes along with systemic, psychiatric, and neurologic abnormalities, and in particular, ataxia. Until now, there has been only one therapy, with miglustat. which has many side effects.
The group of authors found a new therapeutic approach with N-acetyl-L-leucine, which primarily increases mitochondrial energy production. This was a small, placebo-controlled, crossover trial with 2 x 12 weeks of treatment. This new compound showed efficacy and was very well tolerated. This shows that we definitely need long-term studies with this new, well-tolerated drug in this rare disease.
Anticoagulation in Subclinical AF
My fourth study comes from the stroke-prevention field, published in The New England Journal of Medicine. I think you are aware of subclinical atrail fibrillation. These are high-frequency episodes in ECG, usually identified by pacemakers or ECG monitoring systems. The international ARTESIA study included more than 4000 patients randomized either to apixaban 5 mg twice daily or aspirin 81 mg.
After 3.5 years, the investigators showed a small but significant decrease in the rate of stroke, with a relative risk reduction of 37%, but also, unfortunately, a significantly increased risk for major bleeding with apixaban. This means that we need a careful discussion with the patient, the family, and the GP to decide whether these patients should be anticoagulated or not.
Migraine and Depression
My final study, published in the European Journal of Neurology, deals with the comorbidity of depression and migraine. This study in the Netherlands included 108 patients treated with erenumab and 90 with fremanezumab; 68 were controls.
They used two depression scales. They showed that treatment with the monoclonal antibodies improved at least one of the two depression scales. I think this is an important study because it indicates that you can improve comorbid depression in people with severe migraine, even if this study did not show a correlation between the reduction in monthly migraine days and the improvement of depression.
What we learned for clinical practice is that we have to identify depression in people with migraine and we have to deal with it. Whether it’s with the treatment of monoclonal antibodies or antidepressant therapy doesn’t really matter.
Dear colleagues, we had interesting studies this month. I think the most spectacular one was published in Science on long COVID. Thank you very much for listening and watching. I’m Christoph Diener from University Duisburg-Essen.
Dr. Diener is Professor, Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen, Essen, Germany. He disclosed ties with Abbott; Addex Pharma; Alder; Allergan; Almirall; Amgen; Autonomic Technology; AstraZeneca; Bayer Vital; Berlin Chemie; Bristol-Myers Squibb; Boehringer Ingelheim; Chordate; CoAxia; Corimmun; Covidien; Coherex; CoLucid; Daiichi-Sankyo; D-Pharml Electrocore; Fresenius; GlaxoSmithKline; Grunenthal; Janssen-Cilag; Labrys Biologics Lilly; La Roche; 3M Medica; MSD; Medtronic; Menarini; MindFrame; Minster; Neuroscore; Neurobiological Technologies; Novartis; Novo-Nordisk; Johnson & Johnson; Knoll; Paion; Parke-Davis; Pierre Fabre; Pfizer Inc; Schaper and Brummer; sanofi-aventis; Schering-Plough; Servier; Solvay; Syngis; St. Jude; Talecris; Thrombogenics; WebMD Global; Weber and Weber; Wyeth; and Yamanouchi.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Dear colleagues, I’m Christoph Diener from the medical faculty of University Duisburg-Essen in Germany. Today I would like to tell you about five interesting studies that were published in January 2024.
Long COVID
I would like to start with long COVID. There is an ongoing discussion about whether this condition — which means symptoms like dizziness, vertigo, fatigue, headache, and cognitive impairment that persist for more than 6 months — is either a consequence of the infection, functional symptoms, psychosomatic disease, or a depression.
There is an important paper that came out in Science. The group investigated 39 controls and 113 patients who had COVID-19. At 6 months, 40 of them had long COVID. The researchers repeatedly measured more than 6500 proteins in serum. The patients with long COVID had a significant increase in complement activation, which persisted even beyond 6 months. These patients also showed increased tissue lesion markers in the blood and activation of the endothelium.
Also, they had increased platelet activation and autoantibodies with increased anti-cytomegalovirus and anti-Epstein-Barr virus immunoglobulins. These are very strong indicators that COVID-19 leads to long-term changes in our immune system, and different activations of complement factors could explain the variety of symptoms that these patients display. Whether this has consequences for treatment is unclear at the moment.
Parkinson’s Classification
Let me come to another issue, which is the future treatment of Parkinson’s disease, covered in a paper in The Lancet Neurology. I think you are all aware that once patients display symptoms like rigidity, bradykinesia, or tremor, it’s most probably too late for neuroprotective therapy because 70% of the dopaminergic neurons are already dead.
The authors propose a new biological diagnosis of the disease in the preclinical state. This early preclinical diagnosis has three components. One is to show the presence of synuclein either in skin biopsy or in serum. The second is proof of neurodegeneration either by MRI or by PET imaging. The third involves genetic markers.
On top of this, we know that we have preclinical manifestations of Parkinson’s disease, like REM sleep disorders, autonomic disturbances, and cognitive impairment. With this new classification, we should be able to identify the preclinical phase of Parkinson’s disease and include these patients in future trials for neuroprotection.
Niemann-Pick Disease
My third study, in The New England Journal of Medicine, deals with Niemann-Pick disease type C (Trial of N-Acetyl-l-Leucine in Niemann–Pick Disease Type C. This is a rare autosomal recessive disorder that involves impaired lysosomal storage. This disease, which manifests usually in childhood, goes along with systemic, psychiatric, and neurologic abnormalities, and in particular, ataxia. Until now, there has been only one therapy, with miglustat. which has many side effects.
The group of authors found a new therapeutic approach with N-acetyl-L-leucine, which primarily increases mitochondrial energy production. This was a small, placebo-controlled, crossover trial with 2 x 12 weeks of treatment. This new compound showed efficacy and was very well tolerated. This shows that we definitely need long-term studies with this new, well-tolerated drug in this rare disease.
Anticoagulation in Subclinical AF
My fourth study comes from the stroke-prevention field, published in The New England Journal of Medicine. I think you are aware of subclinical atrail fibrillation. These are high-frequency episodes in ECG, usually identified by pacemakers or ECG monitoring systems. The international ARTESIA study included more than 4000 patients randomized either to apixaban 5 mg twice daily or aspirin 81 mg.
After 3.5 years, the investigators showed a small but significant decrease in the rate of stroke, with a relative risk reduction of 37%, but also, unfortunately, a significantly increased risk for major bleeding with apixaban. This means that we need a careful discussion with the patient, the family, and the GP to decide whether these patients should be anticoagulated or not.
Migraine and Depression
My final study, published in the European Journal of Neurology, deals with the comorbidity of depression and migraine. This study in the Netherlands included 108 patients treated with erenumab and 90 with fremanezumab; 68 were controls.
They used two depression scales. They showed that treatment with the monoclonal antibodies improved at least one of the two depression scales. I think this is an important study because it indicates that you can improve comorbid depression in people with severe migraine, even if this study did not show a correlation between the reduction in monthly migraine days and the improvement of depression.
What we learned for clinical practice is that we have to identify depression in people with migraine and we have to deal with it. Whether it’s with the treatment of monoclonal antibodies or antidepressant therapy doesn’t really matter.
Dear colleagues, we had interesting studies this month. I think the most spectacular one was published in Science on long COVID. Thank you very much for listening and watching. I’m Christoph Diener from University Duisburg-Essen.
Dr. Diener is Professor, Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen, Essen, Germany. He disclosed ties with Abbott; Addex Pharma; Alder; Allergan; Almirall; Amgen; Autonomic Technology; AstraZeneca; Bayer Vital; Berlin Chemie; Bristol-Myers Squibb; Boehringer Ingelheim; Chordate; CoAxia; Corimmun; Covidien; Coherex; CoLucid; Daiichi-Sankyo; D-Pharml Electrocore; Fresenius; GlaxoSmithKline; Grunenthal; Janssen-Cilag; Labrys Biologics Lilly; La Roche; 3M Medica; MSD; Medtronic; Menarini; MindFrame; Minster; Neuroscore; Neurobiological Technologies; Novartis; Novo-Nordisk; Johnson & Johnson; Knoll; Paion; Parke-Davis; Pierre Fabre; Pfizer Inc; Schaper and Brummer; sanofi-aventis; Schering-Plough; Servier; Solvay; Syngis; St. Jude; Talecris; Thrombogenics; WebMD Global; Weber and Weber; Wyeth; and Yamanouchi.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
Dear colleagues, I’m Christoph Diener from the medical faculty of University Duisburg-Essen in Germany. Today I would like to tell you about five interesting studies that were published in January 2024.
Long COVID
I would like to start with long COVID. There is an ongoing discussion about whether this condition — which means symptoms like dizziness, vertigo, fatigue, headache, and cognitive impairment that persist for more than 6 months — is either a consequence of the infection, functional symptoms, psychosomatic disease, or a depression.
There is an important paper that came out in Science. The group investigated 39 controls and 113 patients who had COVID-19. At 6 months, 40 of them had long COVID. The researchers repeatedly measured more than 6500 proteins in serum. The patients with long COVID had a significant increase in complement activation, which persisted even beyond 6 months. These patients also showed increased tissue lesion markers in the blood and activation of the endothelium.
Also, they had increased platelet activation and autoantibodies with increased anti-cytomegalovirus and anti-Epstein-Barr virus immunoglobulins. These are very strong indicators that COVID-19 leads to long-term changes in our immune system, and different activations of complement factors could explain the variety of symptoms that these patients display. Whether this has consequences for treatment is unclear at the moment.
Parkinson’s Classification
Let me come to another issue, which is the future treatment of Parkinson’s disease, covered in a paper in The Lancet Neurology. I think you are all aware that once patients display symptoms like rigidity, bradykinesia, or tremor, it’s most probably too late for neuroprotective therapy because 70% of the dopaminergic neurons are already dead.
The authors propose a new biological diagnosis of the disease in the preclinical state. This early preclinical diagnosis has three components. One is to show the presence of synuclein either in skin biopsy or in serum. The second is proof of neurodegeneration either by MRI or by PET imaging. The third involves genetic markers.
On top of this, we know that we have preclinical manifestations of Parkinson’s disease, like REM sleep disorders, autonomic disturbances, and cognitive impairment. With this new classification, we should be able to identify the preclinical phase of Parkinson’s disease and include these patients in future trials for neuroprotection.
Niemann-Pick Disease
My third study, in The New England Journal of Medicine, deals with Niemann-Pick disease type C (Trial of N-Acetyl-l-Leucine in Niemann–Pick Disease Type C. This is a rare autosomal recessive disorder that involves impaired lysosomal storage. This disease, which manifests usually in childhood, goes along with systemic, psychiatric, and neurologic abnormalities, and in particular, ataxia. Until now, there has been only one therapy, with miglustat. which has many side effects.
The group of authors found a new therapeutic approach with N-acetyl-L-leucine, which primarily increases mitochondrial energy production. This was a small, placebo-controlled, crossover trial with 2 x 12 weeks of treatment. This new compound showed efficacy and was very well tolerated. This shows that we definitely need long-term studies with this new, well-tolerated drug in this rare disease.
Anticoagulation in Subclinical AF
My fourth study comes from the stroke-prevention field, published in The New England Journal of Medicine. I think you are aware of subclinical atrail fibrillation. These are high-frequency episodes in ECG, usually identified by pacemakers or ECG monitoring systems. The international ARTESIA study included more than 4000 patients randomized either to apixaban 5 mg twice daily or aspirin 81 mg.
After 3.5 years, the investigators showed a small but significant decrease in the rate of stroke, with a relative risk reduction of 37%, but also, unfortunately, a significantly increased risk for major bleeding with apixaban. This means that we need a careful discussion with the patient, the family, and the GP to decide whether these patients should be anticoagulated or not.
Migraine and Depression
My final study, published in the European Journal of Neurology, deals with the comorbidity of depression and migraine. This study in the Netherlands included 108 patients treated with erenumab and 90 with fremanezumab; 68 were controls.
They used two depression scales. They showed that treatment with the monoclonal antibodies improved at least one of the two depression scales. I think this is an important study because it indicates that you can improve comorbid depression in people with severe migraine, even if this study did not show a correlation between the reduction in monthly migraine days and the improvement of depression.
What we learned for clinical practice is that we have to identify depression in people with migraine and we have to deal with it. Whether it’s with the treatment of monoclonal antibodies or antidepressant therapy doesn’t really matter.
Dear colleagues, we had interesting studies this month. I think the most spectacular one was published in Science on long COVID. Thank you very much for listening and watching. I’m Christoph Diener from University Duisburg-Essen.
Dr. Diener is Professor, Department of Neurology, Stroke Center-Headache Center, University Duisburg-Essen, Essen, Germany. He disclosed ties with Abbott; Addex Pharma; Alder; Allergan; Almirall; Amgen; Autonomic Technology; AstraZeneca; Bayer Vital; Berlin Chemie; Bristol-Myers Squibb; Boehringer Ingelheim; Chordate; CoAxia; Corimmun; Covidien; Coherex; CoLucid; Daiichi-Sankyo; D-Pharml Electrocore; Fresenius; GlaxoSmithKline; Grunenthal; Janssen-Cilag; Labrys Biologics Lilly; La Roche; 3M Medica; MSD; Medtronic; Menarini; MindFrame; Minster; Neuroscore; Neurobiological Technologies; Novartis; Novo-Nordisk; Johnson & Johnson; Knoll; Paion; Parke-Davis; Pierre Fabre; Pfizer Inc; Schaper and Brummer; sanofi-aventis; Schering-Plough; Servier; Solvay; Syngis; St. Jude; Talecris; Thrombogenics; WebMD Global; Weber and Weber; Wyeth; and Yamanouchi.
A version of this article appeared on Medscape.com.
Prednisolone May Improve MOH Withdrawal
, an observational study out of South Korea has found.
The study, a post-hoc analysis of the RELEASE multicenter observational cohort study of MOH patients in South Korea, found that patients who took prednisolone as a bridge therapy in the early phase of withdrawal from headache medications, or detoxification, had statistically significant higher rates of MOH reversal at 3 months after enrollment than those who did not, 73.8% versus 57.8% (P = .034) 
The reversal trend also was noted at 1 month after treatment, the study authors, led by Mi Ji Lee, MD, PhD, an assistant professor at Seoul National University Hospital, Seoul, South Korea, wrote. “Although an observational study cannot draw a definitive conclusion, our study supports the use of prednisolone for the treatment of MOH in a real-world setting,” Dr. Lee and colleagues wrote.
Study methods
The study was a post hoc analysis of the RELEASE study, which stands for Registry for Load and Management of Medication Overuse Headache. RELEASE is a multicenter observational cohort study that has been ongoing in South Korea since April 2020. The post hoc analysis included 309 patients, 59 of whom received prednisolone at a varying dose of 10-40 mg a day, with a varying course of 5-14 days. About 74% of patients (228 of 309) completed the 3-month follow-up period, including 41 in the prednisolone group.
The study used three different forms of medication withdrawal before the patients started prednisolone therapy: abrupt discontinuation; gradual discontinuation concurrent with starting prednisolone; and no withdrawal.
Because of the observational nature of the RELEASE study, participating physicians prescribed prednisolone at their own discretion. The study authors noted prednisolone use was neither randomized nor controlled, which they acknowledged as a limitation.
Dr. Lee and colleagues also acknowledged that newer calcitonin gene–related peptide (CGRP) receptor antagonists may not require detoxification to reverse MOH, but that those therapies are not always available for a variety of reasons, such as reimbursement restrictions, regional distribution issues, and financial issues.
The study also evaluated a number of secondary outcomes. For example, 72% of prednisolone patients achieved MOH reversal 1 month after starting treatment versus 54.9% of the nonprednisolone patients. (P = .33). Prednisolone users also had greater reductions in acute medication days (AMD) at 1 month and scores on headache impact test-6 (HIT-6) at 6 months.
Dr. Lee and colleagues noted that the concept of detoxification, or discontinuing medication overuse, as a treatment for MOH has been controversial due to a lack of high-quality evidence to support the approach. “Nevertheless,” they wrote, “several experts still put withdrawal of medication overuse as an important step of MOH treatment in clinical practice despite limited evidence.”
Commentary
Alan Rapoport, MD, a clinical professor of neurology at the David Geffen School of Medicine at University of California, Los Angeles, noted a number of limitations with the study. “It wasn’t a unified population of patients,” he said, “which makes it a little harder to say this medicine worked — worked on whom?” The lack of a treatment regimen — the varied dosing and treatment durations, along with the different withdrawal approaches — are further limitations, Dr. Rapoport said.
Nonetheless, the study is an important addition to the evidence on how to manage medication withdrawal in MOH, said Dr. Rapoport, a past president of the International Headache Society and founder and director emeritus of the New England Center for Headache in Stamford, Connecticut, who has a keen interest in MOH research.
“I think this shows to some extent, although it doesn’t prove it because it’s a whole mixture of patients who were all treated differently by different doctors, but when you put them all together the patients who took steroids did better than the patients who did not,” he said. “The study authors did the best they could with the information they had.”
He termed the study “well-done by well-known authors in South Korea.” As medications such as CGRP receptor antagonists and monoclonal antibodies that target CGRP and its receptors become more available, MOH patients “may not need actual detoxification or steroids in their treatment,” Dr. Rapoport said.
Dr. Lee and co-authors have no disclosures. Dr. Rapoport is editor-in-chief of Neurology Reviews. He disclosed relationships with AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica.
, an observational study out of South Korea has found.
The study, a post-hoc analysis of the RELEASE multicenter observational cohort study of MOH patients in South Korea, found that patients who took prednisolone as a bridge therapy in the early phase of withdrawal from headache medications, or detoxification, had statistically significant higher rates of MOH reversal at 3 months after enrollment than those who did not, 73.8% versus 57.8% (P = .034)
The reversal trend also was noted at 1 month after treatment, the study authors, led by Mi Ji Lee, MD, PhD, an assistant professor at Seoul National University Hospital, Seoul, South Korea, wrote. “Although an observational study cannot draw a definitive conclusion, our study supports the use of prednisolone for the treatment of MOH in a real-world setting,” Dr. Lee and colleagues wrote.
Study methods
The study was a post hoc analysis of the RELEASE study, which stands for Registry for Load and Management of Medication Overuse Headache. RELEASE is a multicenter observational cohort study that has been ongoing in South Korea since April 2020. The post hoc analysis included 309 patients, 59 of whom received prednisolone at a varying dose of 10-40 mg a day, with a varying course of 5-14 days. About 74% of patients (228 of 309) completed the 3-month follow-up period, including 41 in the prednisolone group.
The study used three different forms of medication withdrawal before the patients started prednisolone therapy: abrupt discontinuation; gradual discontinuation concurrent with starting prednisolone; and no withdrawal.
Because of the observational nature of the RELEASE study, participating physicians prescribed prednisolone at their own discretion. The study authors noted prednisolone use was neither randomized nor controlled, which they acknowledged as a limitation.
Dr. Lee and colleagues also acknowledged that newer calcitonin gene–related peptide (CGRP) receptor antagonists may not require detoxification to reverse MOH, but that those therapies are not always available for a variety of reasons, such as reimbursement restrictions, regional distribution issues, and financial issues.
The study also evaluated a number of secondary outcomes. For example, 72% of prednisolone patients achieved MOH reversal 1 month after starting treatment versus 54.9% of the nonprednisolone patients. (P = .33). Prednisolone users also had greater reductions in acute medication days (AMD) at 1 month and scores on headache impact test-6 (HIT-6) at 6 months.
Dr. Lee and colleagues noted that the concept of detoxification, or discontinuing medication overuse, as a treatment for MOH has been controversial due to a lack of high-quality evidence to support the approach. “Nevertheless,” they wrote, “several experts still put withdrawal of medication overuse as an important step of MOH treatment in clinical practice despite limited evidence.”
Commentary
Alan Rapoport, MD, a clinical professor of neurology at the David Geffen School of Medicine at University of California, Los Angeles, noted a number of limitations with the study. “It wasn’t a unified population of patients,” he said, “which makes it a little harder to say this medicine worked — worked on whom?” The lack of a treatment regimen — the varied dosing and treatment durations, along with the different withdrawal approaches — are further limitations, Dr. Rapoport said.
Nonetheless, the study is an important addition to the evidence on how to manage medication withdrawal in MOH, said Dr. Rapoport, a past president of the International Headache Society and founder and director emeritus of the New England Center for Headache in Stamford, Connecticut, who has a keen interest in MOH research.
“I think this shows to some extent, although it doesn’t prove it because it’s a whole mixture of patients who were all treated differently by different doctors, but when you put them all together the patients who took steroids did better than the patients who did not,” he said. “The study authors did the best they could with the information they had.”
He termed the study “well-done by well-known authors in South Korea.” As medications such as CGRP receptor antagonists and monoclonal antibodies that target CGRP and its receptors become more available, MOH patients “may not need actual detoxification or steroids in their treatment,” Dr. Rapoport said.
Dr. Lee and co-authors have no disclosures. Dr. Rapoport is editor-in-chief of Neurology Reviews. He disclosed relationships with AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica.
, an observational study out of South Korea has found.
The study, a post-hoc analysis of the RELEASE multicenter observational cohort study of MOH patients in South Korea, found that patients who took prednisolone as a bridge therapy in the early phase of withdrawal from headache medications, or detoxification, had statistically significant higher rates of MOH reversal at 3 months after enrollment than those who did not, 73.8% versus 57.8% (P = .034)
The reversal trend also was noted at 1 month after treatment, the study authors, led by Mi Ji Lee, MD, PhD, an assistant professor at Seoul National University Hospital, Seoul, South Korea, wrote. “Although an observational study cannot draw a definitive conclusion, our study supports the use of prednisolone for the treatment of MOH in a real-world setting,” Dr. Lee and colleagues wrote.
Study methods
The study was a post hoc analysis of the RELEASE study, which stands for Registry for Load and Management of Medication Overuse Headache. RELEASE is a multicenter observational cohort study that has been ongoing in South Korea since April 2020. The post hoc analysis included 309 patients, 59 of whom received prednisolone at a varying dose of 10-40 mg a day, with a varying course of 5-14 days. About 74% of patients (228 of 309) completed the 3-month follow-up period, including 41 in the prednisolone group.
The study used three different forms of medication withdrawal before the patients started prednisolone therapy: abrupt discontinuation; gradual discontinuation concurrent with starting prednisolone; and no withdrawal.
Because of the observational nature of the RELEASE study, participating physicians prescribed prednisolone at their own discretion. The study authors noted prednisolone use was neither randomized nor controlled, which they acknowledged as a limitation.
Dr. Lee and colleagues also acknowledged that newer calcitonin gene–related peptide (CGRP) receptor antagonists may not require detoxification to reverse MOH, but that those therapies are not always available for a variety of reasons, such as reimbursement restrictions, regional distribution issues, and financial issues.
The study also evaluated a number of secondary outcomes. For example, 72% of prednisolone patients achieved MOH reversal 1 month after starting treatment versus 54.9% of the nonprednisolone patients. (P = .33). Prednisolone users also had greater reductions in acute medication days (AMD) at 1 month and scores on headache impact test-6 (HIT-6) at 6 months.
Dr. Lee and colleagues noted that the concept of detoxification, or discontinuing medication overuse, as a treatment for MOH has been controversial due to a lack of high-quality evidence to support the approach. “Nevertheless,” they wrote, “several experts still put withdrawal of medication overuse as an important step of MOH treatment in clinical practice despite limited evidence.”
Commentary
Alan Rapoport, MD, a clinical professor of neurology at the David Geffen School of Medicine at University of California, Los Angeles, noted a number of limitations with the study. “It wasn’t a unified population of patients,” he said, “which makes it a little harder to say this medicine worked — worked on whom?” The lack of a treatment regimen — the varied dosing and treatment durations, along with the different withdrawal approaches — are further limitations, Dr. Rapoport said.
Nonetheless, the study is an important addition to the evidence on how to manage medication withdrawal in MOH, said Dr. Rapoport, a past president of the International Headache Society and founder and director emeritus of the New England Center for Headache in Stamford, Connecticut, who has a keen interest in MOH research.
“I think this shows to some extent, although it doesn’t prove it because it’s a whole mixture of patients who were all treated differently by different doctors, but when you put them all together the patients who took steroids did better than the patients who did not,” he said. “The study authors did the best they could with the information they had.”
He termed the study “well-done by well-known authors in South Korea.” As medications such as CGRP receptor antagonists and monoclonal antibodies that target CGRP and its receptors become more available, MOH patients “may not need actual detoxification or steroids in their treatment,” Dr. Rapoport said.
Dr. Lee and co-authors have no disclosures. Dr. Rapoport is editor-in-chief of Neurology Reviews. He disclosed relationships with AbbVie, Biohaven, Cala Health, Dr. Reddy’s, Pfizer, Satsuma, Teva Pharmaceutical Industries, and Theranica.
FROM HEADACHE
New, Updated Guidelines for Comprehensive Epilepsy Care
The guidelines — the first from the National Association of Epilepsy Centers (NAEC) in a decade — describe the comprehensive services and resources specialized epilepsy centers should provide to improve quality of care for people living with epilepsy.
“In addition to advances in medicine, there has been a shift toward addressing overall well-being beyond seizure management,” Fred A. Lado, MD, PhD, NAEC president and guideline panel cochair, said in a news release. “This includes care for comorbid conditions like anxiety and depression, enhanced communication between the patient and care team, and addressing health disparities in the epilepsy community.
The guidance was developed by a panel of multidisciplinary experts, which is the first time that the NAEC has gone beyond the field of neurology to seek input from other medical specialists and allied health personnel, the panel noted.
“Expanded guidelines are also sorely needed to help centers and hospitals obtain the resources to provide this level of comprehensive care,” said Dr. Lado, regional director of epilepsy and professor of neurology at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York.
An executive summary of the guidelines was published online in Neurology.
A Multidisciplinary Approach
Epilepsy is one of the most common chronic neurologic conditions worldwide, affecting an estimated 3.4 million people in the United States alone. Recurring seizures can be debilitating and, in some cases, life-threatening.
To update epilepsy care guidelines, an expert panel of 41 stakeholders with diverse expertise evaluated the latest evidence and reached consensus on 52 recommendations spanning a range of services that make up high-quality epilepsy care.
“This is exhibited in a greater emphasis on multidisciplinary care conferences, screening for comorbidities of epilepsy, and providing access to other specialty services in addition to the core epilepsy center components of outpatient care, diagnostic procedures, and epilepsy surgery,” they wrote.
For the first time, the guidelines advise specialized epilepsy centers to offer genetic testing and counseling, provide more education and communication for patients, give greater attention to special-needs populations, employ a care coordinator to organize and facilitate multidisciplinary care, provide mental health screening, and address health disparities and inequities.
“All recommendations quickly reached consensus despite there being such a diverse panel of stakeholders, which emphasizes that the recommendations reflect the important elements of healthcare services that should be in place for an epilepsy center to provide the highest quality of care,” said Susan Arnold, MD, guideline panel co-chair and a pediatric epileptologist at Yale University School of Medicine, New Haven, Connecticut.
“But epilepsy centers will need the resources to provide this comprehensive level of care. We hope the guidelines will help increase health insurer and institutional support and recognition of these recommendations,” Dr. Arnold added.
The guidelines were funded by NAEC. Dr. Lado has no relevant disclosures. Dr. Arnold holds stock in Pfizer. A complete list of disclosures for the guideline panel is available with the original article.
A version of this article appeared on Medscape.com.
The guidelines — the first from the National Association of Epilepsy Centers (NAEC) in a decade — describe the comprehensive services and resources specialized epilepsy centers should provide to improve quality of care for people living with epilepsy.
“In addition to advances in medicine, there has been a shift toward addressing overall well-being beyond seizure management,” Fred A. Lado, MD, PhD, NAEC president and guideline panel cochair, said in a news release. “This includes care for comorbid conditions like anxiety and depression, enhanced communication between the patient and care team, and addressing health disparities in the epilepsy community.
The guidance was developed by a panel of multidisciplinary experts, which is the first time that the NAEC has gone beyond the field of neurology to seek input from other medical specialists and allied health personnel, the panel noted.
“Expanded guidelines are also sorely needed to help centers and hospitals obtain the resources to provide this level of comprehensive care,” said Dr. Lado, regional director of epilepsy and professor of neurology at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York.
An executive summary of the guidelines was published online in Neurology.
A Multidisciplinary Approach
Epilepsy is one of the most common chronic neurologic conditions worldwide, affecting an estimated 3.4 million people in the United States alone. Recurring seizures can be debilitating and, in some cases, life-threatening.
To update epilepsy care guidelines, an expert panel of 41 stakeholders with diverse expertise evaluated the latest evidence and reached consensus on 52 recommendations spanning a range of services that make up high-quality epilepsy care.
“This is exhibited in a greater emphasis on multidisciplinary care conferences, screening for comorbidities of epilepsy, and providing access to other specialty services in addition to the core epilepsy center components of outpatient care, diagnostic procedures, and epilepsy surgery,” they wrote.
For the first time, the guidelines advise specialized epilepsy centers to offer genetic testing and counseling, provide more education and communication for patients, give greater attention to special-needs populations, employ a care coordinator to organize and facilitate multidisciplinary care, provide mental health screening, and address health disparities and inequities.
“All recommendations quickly reached consensus despite there being such a diverse panel of stakeholders, which emphasizes that the recommendations reflect the important elements of healthcare services that should be in place for an epilepsy center to provide the highest quality of care,” said Susan Arnold, MD, guideline panel co-chair and a pediatric epileptologist at Yale University School of Medicine, New Haven, Connecticut.
“But epilepsy centers will need the resources to provide this comprehensive level of care. We hope the guidelines will help increase health insurer and institutional support and recognition of these recommendations,” Dr. Arnold added.
The guidelines were funded by NAEC. Dr. Lado has no relevant disclosures. Dr. Arnold holds stock in Pfizer. A complete list of disclosures for the guideline panel is available with the original article.
A version of this article appeared on Medscape.com.
The guidelines — the first from the National Association of Epilepsy Centers (NAEC) in a decade — describe the comprehensive services and resources specialized epilepsy centers should provide to improve quality of care for people living with epilepsy.
“In addition to advances in medicine, there has been a shift toward addressing overall well-being beyond seizure management,” Fred A. Lado, MD, PhD, NAEC president and guideline panel cochair, said in a news release. “This includes care for comorbid conditions like anxiety and depression, enhanced communication between the patient and care team, and addressing health disparities in the epilepsy community.
The guidance was developed by a panel of multidisciplinary experts, which is the first time that the NAEC has gone beyond the field of neurology to seek input from other medical specialists and allied health personnel, the panel noted.
“Expanded guidelines are also sorely needed to help centers and hospitals obtain the resources to provide this level of comprehensive care,” said Dr. Lado, regional director of epilepsy and professor of neurology at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York.
An executive summary of the guidelines was published online in Neurology.
A Multidisciplinary Approach
Epilepsy is one of the most common chronic neurologic conditions worldwide, affecting an estimated 3.4 million people in the United States alone. Recurring seizures can be debilitating and, in some cases, life-threatening.
To update epilepsy care guidelines, an expert panel of 41 stakeholders with diverse expertise evaluated the latest evidence and reached consensus on 52 recommendations spanning a range of services that make up high-quality epilepsy care.
“This is exhibited in a greater emphasis on multidisciplinary care conferences, screening for comorbidities of epilepsy, and providing access to other specialty services in addition to the core epilepsy center components of outpatient care, diagnostic procedures, and epilepsy surgery,” they wrote.
For the first time, the guidelines advise specialized epilepsy centers to offer genetic testing and counseling, provide more education and communication for patients, give greater attention to special-needs populations, employ a care coordinator to organize and facilitate multidisciplinary care, provide mental health screening, and address health disparities and inequities.
“All recommendations quickly reached consensus despite there being such a diverse panel of stakeholders, which emphasizes that the recommendations reflect the important elements of healthcare services that should be in place for an epilepsy center to provide the highest quality of care,” said Susan Arnold, MD, guideline panel co-chair and a pediatric epileptologist at Yale University School of Medicine, New Haven, Connecticut.
“But epilepsy centers will need the resources to provide this comprehensive level of care. We hope the guidelines will help increase health insurer and institutional support and recognition of these recommendations,” Dr. Arnold added.
The guidelines were funded by NAEC. Dr. Lado has no relevant disclosures. Dr. Arnold holds stock in Pfizer. A complete list of disclosures for the guideline panel is available with the original article.
A version of this article appeared on Medscape.com.
FROM NEUROLOGY