Neurology

Unlike in adults, seizures, including status epilepticus (SE), may be the first and main manifestation of COVID-19 in children, new research suggests.

Seizures may occur even in children with no history of epilepsy and in the absence of fever or severe COVID-19 illness, necessitating a “high index” of suspicion for the virus to make an early diagnosis and allow for appropriate infection control measures, say the researchers.

“We hope to increase physicians’ awareness of noninfluenza-like presentations of COVID in children. In areas with a high prevalence of COVID, we suggest that children with seizures be tested for COVID,” Tal Gilboa, MD, director of the child neurology unit and codirector of epilepsy, Hadassah Medical Center, Jerusalem, told this news organization.

The study was published online August 27 in the journal Seizure.
 

Presenting symptom

Among 175 children diagnosed with acute SARS-CoV-2 infection in the emergency department over 10 months in 2020, 11 (6%) presented with seizures. Studies in adults with COVID-19 have reported seizures in 0% to 2% of cases, the investigators note.

The 11 children with seizures (seven boys) ranged in age from 6 months to 17 years (median age, 11.5 years). All of them had seizures as the presenting sign of infection and none had severe COVID-19 requiring ventilatory or hemodynamic support. Six of the 11 children presented with fever.

Seven of the children had a prior history of neurological disorder: Five had epilepsy, one had a single unprovoked seizure 3 years before admission, and one had an intellectual disability. Three of the children had uncontrolled seizures despite appropriate treatment with antiseizure medication.

Nine of the 11 children presented with generalized tonic-clonic seizures. One child with a prior history of uncontrolled epilepsy with multiple seizure types had a focal tonic seizure. The youngest patient, a 5-month-old infant, presented with bilateral asymmetrical tonic-clonic seizure.

Of note, say the investigators, five of the 11 children presented with convulsive SE; none had a history of prior SE, and one had no history of seizures.

Although young age, especially under 12 months, is a known risk factor for SE, four of the five patients with SE were between 5 and 17 years old. All five children with SE responded to treatment with antiseizure medications.

All 11 children made a full recovery while in hospital, although further follow-up is essential to determine long-term outcomes, the researchers report.

“Children with no prior history of epilepsy and those with well-controlled epilepsy who present with breakthrough seizures, regardless of their body temperature, should be considered as potentially infected by SARS-CoV-2,” said Dr. Gilboa.

“It is possible, however unlikely, that a child, especially with prior epilepsy, may have an unprovoked seizure while being asymptomatically infected by SARS-CoV-2; in any case, infection control measures should be taken,” Dr. Gilboa added.
 

Need for replication

Weighing in on the study, Carl E. Stafstrom, MD, PhD, professor of neurology and pediatrics, Johns Hopkins University, Baltimore, said it’s important to note that “about half of the children had had epilepsy already, and for whatever reason, had a seizure, which required an ED visit, and then they found COVID.”

“Nevertheless, this article is interesting and surprising in what they found because nobody else has found nearly as frequent a seizure presentation,” said Dr. Stafstrom, director of the John M. Freeman Pediatric Epilepsy Center, Johns Hopkins Medicine.

“We would want to see some replication from other institutions and other populations,” he added.

The study had no specific funding. Dr. Gilboa and Dr. Stafstrom have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Unlike in adults, seizures, including status epilepticus (SE), may be the first and main manifestation of COVID-19 in children, new research suggests.

Seizures may occur even in children with no history of epilepsy and in the absence of fever or severe COVID-19 illness, necessitating a “high index” of suspicion for the virus to make an early diagnosis and allow for appropriate infection control measures, say the researchers.

“We hope to increase physicians’ awareness of noninfluenza-like presentations of COVID in children. In areas with a high prevalence of COVID, we suggest that children with seizures be tested for COVID,” Tal Gilboa, MD, director of the child neurology unit and codirector of epilepsy, Hadassah Medical Center, Jerusalem, told this news organization.

The study was published online August 27 in the journal Seizure.
 

Presenting symptom

Among 175 children diagnosed with acute SARS-CoV-2 infection in the emergency department over 10 months in 2020, 11 (6%) presented with seizures. Studies in adults with COVID-19 have reported seizures in 0% to 2% of cases, the investigators note.

The 11 children with seizures (seven boys) ranged in age from 6 months to 17 years (median age, 11.5 years). All of them had seizures as the presenting sign of infection and none had severe COVID-19 requiring ventilatory or hemodynamic support. Six of the 11 children presented with fever.

Seven of the children had a prior history of neurological disorder: Five had epilepsy, one had a single unprovoked seizure 3 years before admission, and one had an intellectual disability. Three of the children had uncontrolled seizures despite appropriate treatment with antiseizure medication.

Nine of the 11 children presented with generalized tonic-clonic seizures. One child with a prior history of uncontrolled epilepsy with multiple seizure types had a focal tonic seizure. The youngest patient, a 5-month-old infant, presented with bilateral asymmetrical tonic-clonic seizure.

Of note, say the investigators, five of the 11 children presented with convulsive SE; none had a history of prior SE, and one had no history of seizures.

Although young age, especially under 12 months, is a known risk factor for SE, four of the five patients with SE were between 5 and 17 years old. All five children with SE responded to treatment with antiseizure medications.

All 11 children made a full recovery while in hospital, although further follow-up is essential to determine long-term outcomes, the researchers report.

“Children with no prior history of epilepsy and those with well-controlled epilepsy who present with breakthrough seizures, regardless of their body temperature, should be considered as potentially infected by SARS-CoV-2,” said Dr. Gilboa.

“It is possible, however unlikely, that a child, especially with prior epilepsy, may have an unprovoked seizure while being asymptomatically infected by SARS-CoV-2; in any case, infection control measures should be taken,” Dr. Gilboa added.
 

Need for replication

Weighing in on the study, Carl E. Stafstrom, MD, PhD, professor of neurology and pediatrics, Johns Hopkins University, Baltimore, said it’s important to note that “about half of the children had had epilepsy already, and for whatever reason, had a seizure, which required an ED visit, and then they found COVID.”

“Nevertheless, this article is interesting and surprising in what they found because nobody else has found nearly as frequent a seizure presentation,” said Dr. Stafstrom, director of the John M. Freeman Pediatric Epilepsy Center, Johns Hopkins Medicine.

“We would want to see some replication from other institutions and other populations,” he added.

The study had no specific funding. Dr. Gilboa and Dr. Stafstrom have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Unlike in adults, seizures, including status epilepticus (SE), may be the first and main manifestation of COVID-19 in children, new research suggests.

Seizures may occur even in children with no history of epilepsy and in the absence of fever or severe COVID-19 illness, necessitating a “high index” of suspicion for the virus to make an early diagnosis and allow for appropriate infection control measures, say the researchers.

“We hope to increase physicians’ awareness of noninfluenza-like presentations of COVID in children. In areas with a high prevalence of COVID, we suggest that children with seizures be tested for COVID,” Tal Gilboa, MD, director of the child neurology unit and codirector of epilepsy, Hadassah Medical Center, Jerusalem, told this news organization.

The study was published online August 27 in the journal Seizure.
 

Presenting symptom

Among 175 children diagnosed with acute SARS-CoV-2 infection in the emergency department over 10 months in 2020, 11 (6%) presented with seizures. Studies in adults with COVID-19 have reported seizures in 0% to 2% of cases, the investigators note.

The 11 children with seizures (seven boys) ranged in age from 6 months to 17 years (median age, 11.5 years). All of them had seizures as the presenting sign of infection and none had severe COVID-19 requiring ventilatory or hemodynamic support. Six of the 11 children presented with fever.

Seven of the children had a prior history of neurological disorder: Five had epilepsy, one had a single unprovoked seizure 3 years before admission, and one had an intellectual disability. Three of the children had uncontrolled seizures despite appropriate treatment with antiseizure medication.

Nine of the 11 children presented with generalized tonic-clonic seizures. One child with a prior history of uncontrolled epilepsy with multiple seizure types had a focal tonic seizure. The youngest patient, a 5-month-old infant, presented with bilateral asymmetrical tonic-clonic seizure.

Of note, say the investigators, five of the 11 children presented with convulsive SE; none had a history of prior SE, and one had no history of seizures.

Although young age, especially under 12 months, is a known risk factor for SE, four of the five patients with SE were between 5 and 17 years old. All five children with SE responded to treatment with antiseizure medications.

All 11 children made a full recovery while in hospital, although further follow-up is essential to determine long-term outcomes, the researchers report.

“Children with no prior history of epilepsy and those with well-controlled epilepsy who present with breakthrough seizures, regardless of their body temperature, should be considered as potentially infected by SARS-CoV-2,” said Dr. Gilboa.

“It is possible, however unlikely, that a child, especially with prior epilepsy, may have an unprovoked seizure while being asymptomatically infected by SARS-CoV-2; in any case, infection control measures should be taken,” Dr. Gilboa added.
 

Need for replication

Weighing in on the study, Carl E. Stafstrom, MD, PhD, professor of neurology and pediatrics, Johns Hopkins University, Baltimore, said it’s important to note that “about half of the children had had epilepsy already, and for whatever reason, had a seizure, which required an ED visit, and then they found COVID.”

“Nevertheless, this article is interesting and surprising in what they found because nobody else has found nearly as frequent a seizure presentation,” said Dr. Stafstrom, director of the John M. Freeman Pediatric Epilepsy Center, Johns Hopkins Medicine.

“We would want to see some replication from other institutions and other populations,” he added.

The study had no specific funding. Dr. Gilboa and Dr. Stafstrom have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Cannabis-based medicinal products (CBMPs) have shown early promise for refractory childhood epilepsy, but positive media attention, as well as pressure from politicians and marijuana advocacy groups, should not supplant clinical trials and acceptable standards of evidence, according to two leading experts.

In a recent invited review article, Martin Kirkpatrick, MD, of the University of Dundee (Scotland), and Finbar O’Callaghan, MD, PhD, of University College London suggested that childhood epilepsy may be easy terrain for commercial interests to break ground, and from there, build their presence.

“Children with epilepsy are at risk of being used as the ‘Trojan horse’ for the cannabis industry,” Dr. Kirkpatrick and Dr. O’Callaghan wrote in Developmental Medicine & Child Neurology.

They noted that some of the first publicized success stories involving cannabis oil for epilepsy coincided with the rise of the medicinal and recreational cannabis markets, which will constitute an estimated 55-billion-dollar industry by 2027.

“Pediatric neurologists, imbued with the need to practice evidence-based medicine and wary of prescribing unlicensed medicines that had inadequate safety data, suddenly found themselves at odds with an array of vested interests and, most unfortunately, with the families of patients who were keen to try anything that would alleviate the effects of their child’s seizures,” the investigators wrote.

According to the review, fundamental questions about cannabis remain unanswered, including concerns about safety with long-term use, and the medicinal value of various plant components, such as myrcene, a terpene that gives cannabis its characteristic smell.

“A widely discussed issue is whether the terpenes add any therapeutic benefit, contributing to the so-called entourage effect of ‘whole-plant’ medicines,” the investigators wrote. “The concept is that all the constituents of the plant together create ‘the sum of all the parts that leads to the magic or power of cannabis.’ Although commonly referred to, there is little or no robust evidence to support the entourage effect as a credible clinical concept.”

Clinical evidence for treatment of pediatric epilepsy is also lacking, according to Dr. Kirkpatrick and Dr. O’Callaghan.

“Unfortunately, apart from the studies of pure cannabidiol (CBD) in Lennox–Gastaut and Dravet syndromes and tuberous sclerosis complex, level I evidence in the field of CBMPs and refractory epilepsy is lacking,” they wrote.

While other experts have pointed out that lower-level evidence – such as patient-reported outcomes and observational data – have previously been sufficient for drug licensing, Dr. Kirkpatrick and Dr. O’Callaghan noted that such exceptions “almost always” involve conditions without any effective treatments, or drugs that are undeniably effective.

“This is not the scenario with CBMPs,” they wrote, referring to current clinical data as “low-level” evidence “suggesting … possible efficacy.”

They highlighted concerns about placebo effect with open-label epilepsy studies, citing a randomized controlled trial for Dravet syndrome, in which 27% of patients given placebo had a 50% reduction in seizure frequency.

“We need carefully designed, good-quality CBMP studies that produce results on which we can rely,” Dr. Kirkpatrick and Dr. O’Callaghan concluded. “We can then work with families to choose the best treatments for children and young people with epilepsy. We owe this to them.”
 

A therapy of last resort

Jerzy P. Szaflarski, MD, PhD, of the University of Alabama at Birmingham, agreed that data are lacking for the use of CBMPs with patients who have epilepsy and other neurologic conditions; however, he also suggested that Dr. Kirkpatrick and Dr. O’Callaghan did not provide adequate real-world clinical context.

“Medical cannabis is not used as a first-, second-, or third-line therapy,” Dr. Szaflarski said. “It’s mostly used as a last resort in the sense that patients have already failed multiple other therapies.” In that respect, patients and parents are desperate to try anything that might work. “We have medical cannabis, and our patients want to try it, and at the point when multiple therapies have failed, it’s a reasonable option.”

While Dr. Szaflarski agreed that more high-quality clinical trials are needed, he also noted the practical challenges involved in such trials, largely because of variations in cannabis plants.

“The content of the cannabis plant changes depending on the day that it’s collected and the exposure to sun and how much water it has and what’s in the soil and many other things,” Dr. Szaflarski said. “It’s hard to get a very good, standardized product, and that’s why there needs to be a good-quality product delivered by the industry, which I have not seen thus far.”

For this reason, Dr. Szaflarski steers parents and patients away from over-the-counter CBMPs and toward Epidiolex, the only FDA-approved form of CBD.

“There is evidence that Epidiolex works,” he said. “I don’t know whether the products that are sold in a local cannabis store have the same high purity as Epidiolex. I tell [parents] that we should try Epidiolex first because it’s the one that is approved. But if it doesn’t work, we can go in that [other] direction.”

For those going the commercial route, Dr. Szaflarski advised close attention to product ingredients, to ensure that CBMPs are “devoid of any impurities, pesticides, fungicides, and other products that could be potentially dangerous.”

Parents considering CBMPs for their children also need to weigh concerns about long-term neurological safety, he added, noting that, on one hand, commercial products lack data, while on the other, epilepsy itself may cause harm.

“They need to consider the potential effects [of CBMPs] on their child’s brain and development versus … the effects of seizures on the brain,” Dr. Szaflarski said.

Dr. Kirkpatrick and Dr. O’Callaghan disclosed an application for a National Institute for Health Research–funded randomized controlled trial on CBMPs and joint authorship of British Paediatric Neurology Association Guidance on the use of CBMPs in children and young people with epilepsy. Dr. Szaflarski disclosed a relationship with Greenwich Biosciences and several other cannabis companies.

Cannabis-based medicinal products (CBMPs) have shown early promise for refractory childhood epilepsy, but positive media attention, as well as pressure from politicians and marijuana advocacy groups, should not supplant clinical trials and acceptable standards of evidence, according to two leading experts.

In a recent invited review article, Martin Kirkpatrick, MD, of the University of Dundee (Scotland), and Finbar O’Callaghan, MD, PhD, of University College London suggested that childhood epilepsy may be easy terrain for commercial interests to break ground, and from there, build their presence.

“Children with epilepsy are at risk of being used as the ‘Trojan horse’ for the cannabis industry,” Dr. Kirkpatrick and Dr. O’Callaghan wrote in Developmental Medicine & Child Neurology.

They noted that some of the first publicized success stories involving cannabis oil for epilepsy coincided with the rise of the medicinal and recreational cannabis markets, which will constitute an estimated 55-billion-dollar industry by 2027.

“Pediatric neurologists, imbued with the need to practice evidence-based medicine and wary of prescribing unlicensed medicines that had inadequate safety data, suddenly found themselves at odds with an array of vested interests and, most unfortunately, with the families of patients who were keen to try anything that would alleviate the effects of their child’s seizures,” the investigators wrote.

According to the review, fundamental questions about cannabis remain unanswered, including concerns about safety with long-term use, and the medicinal value of various plant components, such as myrcene, a terpene that gives cannabis its characteristic smell.

“A widely discussed issue is whether the terpenes add any therapeutic benefit, contributing to the so-called entourage effect of ‘whole-plant’ medicines,” the investigators wrote. “The concept is that all the constituents of the plant together create ‘the sum of all the parts that leads to the magic or power of cannabis.’ Although commonly referred to, there is little or no robust evidence to support the entourage effect as a credible clinical concept.”

Clinical evidence for treatment of pediatric epilepsy is also lacking, according to Dr. Kirkpatrick and Dr. O’Callaghan.

“Unfortunately, apart from the studies of pure cannabidiol (CBD) in Lennox–Gastaut and Dravet syndromes and tuberous sclerosis complex, level I evidence in the field of CBMPs and refractory epilepsy is lacking,” they wrote.

While other experts have pointed out that lower-level evidence – such as patient-reported outcomes and observational data – have previously been sufficient for drug licensing, Dr. Kirkpatrick and Dr. O’Callaghan noted that such exceptions “almost always” involve conditions without any effective treatments, or drugs that are undeniably effective.

“This is not the scenario with CBMPs,” they wrote, referring to current clinical data as “low-level” evidence “suggesting … possible efficacy.”

They highlighted concerns about placebo effect with open-label epilepsy studies, citing a randomized controlled trial for Dravet syndrome, in which 27% of patients given placebo had a 50% reduction in seizure frequency.

“We need carefully designed, good-quality CBMP studies that produce results on which we can rely,” Dr. Kirkpatrick and Dr. O’Callaghan concluded. “We can then work with families to choose the best treatments for children and young people with epilepsy. We owe this to them.”
 

A therapy of last resort

Jerzy P. Szaflarski, MD, PhD, of the University of Alabama at Birmingham, agreed that data are lacking for the use of CBMPs with patients who have epilepsy and other neurologic conditions; however, he also suggested that Dr. Kirkpatrick and Dr. O’Callaghan did not provide adequate real-world clinical context.

“Medical cannabis is not used as a first-, second-, or third-line therapy,” Dr. Szaflarski said. “It’s mostly used as a last resort in the sense that patients have already failed multiple other therapies.” In that respect, patients and parents are desperate to try anything that might work. “We have medical cannabis, and our patients want to try it, and at the point when multiple therapies have failed, it’s a reasonable option.”

While Dr. Szaflarski agreed that more high-quality clinical trials are needed, he also noted the practical challenges involved in such trials, largely because of variations in cannabis plants.

“The content of the cannabis plant changes depending on the day that it’s collected and the exposure to sun and how much water it has and what’s in the soil and many other things,” Dr. Szaflarski said. “It’s hard to get a very good, standardized product, and that’s why there needs to be a good-quality product delivered by the industry, which I have not seen thus far.”

For this reason, Dr. Szaflarski steers parents and patients away from over-the-counter CBMPs and toward Epidiolex, the only FDA-approved form of CBD.

“There is evidence that Epidiolex works,” he said. “I don’t know whether the products that are sold in a local cannabis store have the same high purity as Epidiolex. I tell [parents] that we should try Epidiolex first because it’s the one that is approved. But if it doesn’t work, we can go in that [other] direction.”

For those going the commercial route, Dr. Szaflarski advised close attention to product ingredients, to ensure that CBMPs are “devoid of any impurities, pesticides, fungicides, and other products that could be potentially dangerous.”

Parents considering CBMPs for their children also need to weigh concerns about long-term neurological safety, he added, noting that, on one hand, commercial products lack data, while on the other, epilepsy itself may cause harm.

“They need to consider the potential effects [of CBMPs] on their child’s brain and development versus … the effects of seizures on the brain,” Dr. Szaflarski said.

Dr. Kirkpatrick and Dr. O’Callaghan disclosed an application for a National Institute for Health Research–funded randomized controlled trial on CBMPs and joint authorship of British Paediatric Neurology Association Guidance on the use of CBMPs in children and young people with epilepsy. Dr. Szaflarski disclosed a relationship with Greenwich Biosciences and several other cannabis companies.

Cannabis-based medicinal products (CBMPs) have shown early promise for refractory childhood epilepsy, but positive media attention, as well as pressure from politicians and marijuana advocacy groups, should not supplant clinical trials and acceptable standards of evidence, according to two leading experts.

In a recent invited review article, Martin Kirkpatrick, MD, of the University of Dundee (Scotland), and Finbar O’Callaghan, MD, PhD, of University College London suggested that childhood epilepsy may be easy terrain for commercial interests to break ground, and from there, build their presence.

“Children with epilepsy are at risk of being used as the ‘Trojan horse’ for the cannabis industry,” Dr. Kirkpatrick and Dr. O’Callaghan wrote in Developmental Medicine & Child Neurology.

They noted that some of the first publicized success stories involving cannabis oil for epilepsy coincided with the rise of the medicinal and recreational cannabis markets, which will constitute an estimated 55-billion-dollar industry by 2027.

“Pediatric neurologists, imbued with the need to practice evidence-based medicine and wary of prescribing unlicensed medicines that had inadequate safety data, suddenly found themselves at odds with an array of vested interests and, most unfortunately, with the families of patients who were keen to try anything that would alleviate the effects of their child’s seizures,” the investigators wrote.

According to the review, fundamental questions about cannabis remain unanswered, including concerns about safety with long-term use, and the medicinal value of various plant components, such as myrcene, a terpene that gives cannabis its characteristic smell.

“A widely discussed issue is whether the terpenes add any therapeutic benefit, contributing to the so-called entourage effect of ‘whole-plant’ medicines,” the investigators wrote. “The concept is that all the constituents of the plant together create ‘the sum of all the parts that leads to the magic or power of cannabis.’ Although commonly referred to, there is little or no robust evidence to support the entourage effect as a credible clinical concept.”

Clinical evidence for treatment of pediatric epilepsy is also lacking, according to Dr. Kirkpatrick and Dr. O’Callaghan.

“Unfortunately, apart from the studies of pure cannabidiol (CBD) in Lennox–Gastaut and Dravet syndromes and tuberous sclerosis complex, level I evidence in the field of CBMPs and refractory epilepsy is lacking,” they wrote.

While other experts have pointed out that lower-level evidence – such as patient-reported outcomes and observational data – have previously been sufficient for drug licensing, Dr. Kirkpatrick and Dr. O’Callaghan noted that such exceptions “almost always” involve conditions without any effective treatments, or drugs that are undeniably effective.

“This is not the scenario with CBMPs,” they wrote, referring to current clinical data as “low-level” evidence “suggesting … possible efficacy.”

They highlighted concerns about placebo effect with open-label epilepsy studies, citing a randomized controlled trial for Dravet syndrome, in which 27% of patients given placebo had a 50% reduction in seizure frequency.

“We need carefully designed, good-quality CBMP studies that produce results on which we can rely,” Dr. Kirkpatrick and Dr. O’Callaghan concluded. “We can then work with families to choose the best treatments for children and young people with epilepsy. We owe this to them.”
 

A therapy of last resort

Jerzy P. Szaflarski, MD, PhD, of the University of Alabama at Birmingham, agreed that data are lacking for the use of CBMPs with patients who have epilepsy and other neurologic conditions; however, he also suggested that Dr. Kirkpatrick and Dr. O’Callaghan did not provide adequate real-world clinical context.

“Medical cannabis is not used as a first-, second-, or third-line therapy,” Dr. Szaflarski said. “It’s mostly used as a last resort in the sense that patients have already failed multiple other therapies.” In that respect, patients and parents are desperate to try anything that might work. “We have medical cannabis, and our patients want to try it, and at the point when multiple therapies have failed, it’s a reasonable option.”

While Dr. Szaflarski agreed that more high-quality clinical trials are needed, he also noted the practical challenges involved in such trials, largely because of variations in cannabis plants.

“The content of the cannabis plant changes depending on the day that it’s collected and the exposure to sun and how much water it has and what’s in the soil and many other things,” Dr. Szaflarski said. “It’s hard to get a very good, standardized product, and that’s why there needs to be a good-quality product delivered by the industry, which I have not seen thus far.”

For this reason, Dr. Szaflarski steers parents and patients away from over-the-counter CBMPs and toward Epidiolex, the only FDA-approved form of CBD.

“There is evidence that Epidiolex works,” he said. “I don’t know whether the products that are sold in a local cannabis store have the same high purity as Epidiolex. I tell [parents] that we should try Epidiolex first because it’s the one that is approved. But if it doesn’t work, we can go in that [other] direction.”

For those going the commercial route, Dr. Szaflarski advised close attention to product ingredients, to ensure that CBMPs are “devoid of any impurities, pesticides, fungicides, and other products that could be potentially dangerous.”

Parents considering CBMPs for their children also need to weigh concerns about long-term neurological safety, he added, noting that, on one hand, commercial products lack data, while on the other, epilepsy itself may cause harm.

“They need to consider the potential effects [of CBMPs] on their child’s brain and development versus … the effects of seizures on the brain,” Dr. Szaflarski said.

Dr. Kirkpatrick and Dr. O’Callaghan disclosed an application for a National Institute for Health Research–funded randomized controlled trial on CBMPs and joint authorship of British Paediatric Neurology Association Guidance on the use of CBMPs in children and young people with epilepsy. Dr. Szaflarski disclosed a relationship with Greenwich Biosciences and several other cannabis companies.

Observational data indicate that the number of hospitalizations for cardiac arrests linked to opioid use roughly doubled from 2012 to 2018.

“This was an observational study, so we cannot conclude that all of the arrests were caused by opioids, but the findings do suggest the opioid epidemic is a contributor to increasing rates,” Senada S. Malik, of the University of New England, Portland, Maine, reported at the virtual annual congress of the European Society of Cardiology.

The data were drawn from the Nationwide Inpatient Sample (NIS) from 2012 to 2018, the most recent period available. Cardiac arrests were considered opioid related if there was a secondary diagnosis of opioid disease. The rates of opioid-associated hospitalizations for these types of cardiac arrests climbed from about 800 per year in 2012 to 1,500 per year in 2018, a trend that was statistically significant (P < .05).

The profile of patients with an opioid-associated cardiac arrest was different from those without secondary diagnosis of opioid disease. This included a younger age and lower rates of comorbidities: heart failure (21.2% vs. 40.6%; P < .05), renal failure (14.3% vs. 30.2%; P < .05), diabetes (19.5% vs. 35.4%; P < .05), and hypertension (43.4% vs. 64.9%; P < .05).
 

Mortality from opioid-associated cardiac arrest is lower

These features might explain the lower rate of in-hospital mortality for opioid-associated cardiac arrests (56.7% vs. 61.2%), according to Ms. Malik, who performed this research in collaboration with Wilbert S. Aronow, MD, director of cardiology research, Westchester Medical Center, Valhalla, N.Y.

When compared to those without a history of opioid use on admission, those with opioid-associated cardiac arrest were more likely to be depressed (18.8% vs. 9.0%), to smoke (37.0% vs. 21.8%) and to abuse alcohol (16.9% vs. 7.1%), according to the NIS data.

While these findings are based on cardiac arrests brought to a hospital, some opioid-induced cardiac arrests never result in hospital admission, according to data included in a recently issued scientific statement from the American Heart Association.

Rate of opioid-associated cardiac arrests underestimated

In that statement, which was focused on opioid-associated out-of-hospital cardiac arrests (OA-OHCA), numerous studies were cited to support the conclusion that these events are common and underestimated. One problem is that opioid-induced cardiac arrests are not always accurately differentiated from cardiac arrests induced by use of other substances, such as barbiturates, cocaine, or alcohol.

For this and other reasons, the data are inconsistent. One study based on emergency medical service (EMS) response data concluded that 9% of all out-of-hospital cardiac arrests are opioid associated.

In another study using potentially more accurate autopsy data, 60% of the non–cardiac-associated cardiac arrests were found to occur in individuals with potentially lethal serum concentrations of opioids. As 40% of out-of-hospital cardiac arrests were considered non–cardiac related, this suggested that 15% of all out-of-hospital cardiac arrests are opioid related.

In the NIS data, the incident curves of opioid-related cardiac arrests appeared to be flattening in 2018, the last year of data collection, but there was no indication they were declining.
 

Patterns of opioid-induced cardiac arrests evolving

The patterns of opioid-induced cardiac arrest have changed and are likely to continue to change in response to the evolving opioid epidemic, according to the AHA scientific statement. The authors described three waves of opioid abuse. The first, which was related to the promotion of prescription opioids to treat chronic pain that ultimately led to high rates of opioid addiction, peaked in 2012 when rates of these prescriptions began to fall. At that time a second wave, attributed to patients switching to less expensive nonprescription heroin, was already underway. A third wave, attributed to growth in the use of synthetic opioids, such as fentanyl, began in 2013 and is ongoing, according to data cited in the AHA statement.

Recognizing the role of opioids in rising rates of cardiac arrest is important for promoting strategies of effective treatment and prevention, according to Cameron Dezfulian, MD, medical director of the adult congenital heart disease program at Texas Children’s Hospital, Houston. Dr. Dezfulian was vice chair and leader of the writing committee for the AHA scientific statement on OA-OHCA. He said there are plenty of data to support the need for greater attention to the role of opioids in cardiac arrest.

“The recent data affirms the trends many of us have observed without our emergency rooms and ICUs: a steady increase in the proportion of OA-OHCA, primarily in young and otherwise healthy individuals,” he said.

He calls not only for more awareness at the front lines of health are but also for a more comprehensive approach.

“Public health policies and community- and hospital-based interventions are needed to reduce the mortality due to OA-OHCA, which is distinct from the traditional cardiac etiology,” Dr. Dezfulian said.

In opioid-induced cardiac arrest, as in other types of cardiac arrest, prompt initiation of cardiopulmonary resuscitation is essential, but early administration of the opioid antagonist naloxone can also be lifesaving, according to treatment strategies outlined in the AHA scientific statement. The fact that OA-OHCA typically occur in patients with structurally and electrophysiologically normal hearts is emphasized in the AHA statement. So is the enormous public health toll of OA-OHCA.

Death due to opioid overdose, which includes cardiac arrests, is now the leading cause of mortality in the U.S. among individuals between the ages of 25 and 64 years, according to the statement.

Ms. Malik reports no potential conflicts of interest. Dr. Dezfulian reports a financial relationship with Mallinckrodt.

Observational data indicate that the number of hospitalizations for cardiac arrests linked to opioid use roughly doubled from 2012 to 2018.

“This was an observational study, so we cannot conclude that all of the arrests were caused by opioids, but the findings do suggest the opioid epidemic is a contributor to increasing rates,” Senada S. Malik, of the University of New England, Portland, Maine, reported at the virtual annual congress of the European Society of Cardiology.

The data were drawn from the Nationwide Inpatient Sample (NIS) from 2012 to 2018, the most recent period available. Cardiac arrests were considered opioid related if there was a secondary diagnosis of opioid disease. The rates of opioid-associated hospitalizations for these types of cardiac arrests climbed from about 800 per year in 2012 to 1,500 per year in 2018, a trend that was statistically significant (P < .05).

The profile of patients with an opioid-associated cardiac arrest was different from those without secondary diagnosis of opioid disease. This included a younger age and lower rates of comorbidities: heart failure (21.2% vs. 40.6%; P < .05), renal failure (14.3% vs. 30.2%; P < .05), diabetes (19.5% vs. 35.4%; P < .05), and hypertension (43.4% vs. 64.9%; P < .05).
 

Mortality from opioid-associated cardiac arrest is lower

These features might explain the lower rate of in-hospital mortality for opioid-associated cardiac arrests (56.7% vs. 61.2%), according to Ms. Malik, who performed this research in collaboration with Wilbert S. Aronow, MD, director of cardiology research, Westchester Medical Center, Valhalla, N.Y.

When compared to those without a history of opioid use on admission, those with opioid-associated cardiac arrest were more likely to be depressed (18.8% vs. 9.0%), to smoke (37.0% vs. 21.8%) and to abuse alcohol (16.9% vs. 7.1%), according to the NIS data.

While these findings are based on cardiac arrests brought to a hospital, some opioid-induced cardiac arrests never result in hospital admission, according to data included in a recently issued scientific statement from the American Heart Association.

Rate of opioid-associated cardiac arrests underestimated

In that statement, which was focused on opioid-associated out-of-hospital cardiac arrests (OA-OHCA), numerous studies were cited to support the conclusion that these events are common and underestimated. One problem is that opioid-induced cardiac arrests are not always accurately differentiated from cardiac arrests induced by use of other substances, such as barbiturates, cocaine, or alcohol.

For this and other reasons, the data are inconsistent. One study based on emergency medical service (EMS) response data concluded that 9% of all out-of-hospital cardiac arrests are opioid associated.

In another study using potentially more accurate autopsy data, 60% of the non–cardiac-associated cardiac arrests were found to occur in individuals with potentially lethal serum concentrations of opioids. As 40% of out-of-hospital cardiac arrests were considered non–cardiac related, this suggested that 15% of all out-of-hospital cardiac arrests are opioid related.

In the NIS data, the incident curves of opioid-related cardiac arrests appeared to be flattening in 2018, the last year of data collection, but there was no indication they were declining.
 

Patterns of opioid-induced cardiac arrests evolving

The patterns of opioid-induced cardiac arrest have changed and are likely to continue to change in response to the evolving opioid epidemic, according to the AHA scientific statement. The authors described three waves of opioid abuse. The first, which was related to the promotion of prescription opioids to treat chronic pain that ultimately led to high rates of opioid addiction, peaked in 2012 when rates of these prescriptions began to fall. At that time a second wave, attributed to patients switching to less expensive nonprescription heroin, was already underway. A third wave, attributed to growth in the use of synthetic opioids, such as fentanyl, began in 2013 and is ongoing, according to data cited in the AHA statement.

Recognizing the role of opioids in rising rates of cardiac arrest is important for promoting strategies of effective treatment and prevention, according to Cameron Dezfulian, MD, medical director of the adult congenital heart disease program at Texas Children’s Hospital, Houston. Dr. Dezfulian was vice chair and leader of the writing committee for the AHA scientific statement on OA-OHCA. He said there are plenty of data to support the need for greater attention to the role of opioids in cardiac arrest.

“The recent data affirms the trends many of us have observed without our emergency rooms and ICUs: a steady increase in the proportion of OA-OHCA, primarily in young and otherwise healthy individuals,” he said.

He calls not only for more awareness at the front lines of health are but also for a more comprehensive approach.

“Public health policies and community- and hospital-based interventions are needed to reduce the mortality due to OA-OHCA, which is distinct from the traditional cardiac etiology,” Dr. Dezfulian said.

In opioid-induced cardiac arrest, as in other types of cardiac arrest, prompt initiation of cardiopulmonary resuscitation is essential, but early administration of the opioid antagonist naloxone can also be lifesaving, according to treatment strategies outlined in the AHA scientific statement. The fact that OA-OHCA typically occur in patients with structurally and electrophysiologically normal hearts is emphasized in the AHA statement. So is the enormous public health toll of OA-OHCA.

Death due to opioid overdose, which includes cardiac arrests, is now the leading cause of mortality in the U.S. among individuals between the ages of 25 and 64 years, according to the statement.

Ms. Malik reports no potential conflicts of interest. Dr. Dezfulian reports a financial relationship with Mallinckrodt.

Observational data indicate that the number of hospitalizations for cardiac arrests linked to opioid use roughly doubled from 2012 to 2018.

“This was an observational study, so we cannot conclude that all of the arrests were caused by opioids, but the findings do suggest the opioid epidemic is a contributor to increasing rates,” Senada S. Malik, of the University of New England, Portland, Maine, reported at the virtual annual congress of the European Society of Cardiology.

The data were drawn from the Nationwide Inpatient Sample (NIS) from 2012 to 2018, the most recent period available. Cardiac arrests were considered opioid related if there was a secondary diagnosis of opioid disease. The rates of opioid-associated hospitalizations for these types of cardiac arrests climbed from about 800 per year in 2012 to 1,500 per year in 2018, a trend that was statistically significant (P < .05).

The profile of patients with an opioid-associated cardiac arrest was different from those without secondary diagnosis of opioid disease. This included a younger age and lower rates of comorbidities: heart failure (21.2% vs. 40.6%; P < .05), renal failure (14.3% vs. 30.2%; P < .05), diabetes (19.5% vs. 35.4%; P < .05), and hypertension (43.4% vs. 64.9%; P < .05).
 

Mortality from opioid-associated cardiac arrest is lower

These features might explain the lower rate of in-hospital mortality for opioid-associated cardiac arrests (56.7% vs. 61.2%), according to Ms. Malik, who performed this research in collaboration with Wilbert S. Aronow, MD, director of cardiology research, Westchester Medical Center, Valhalla, N.Y.

When compared to those without a history of opioid use on admission, those with opioid-associated cardiac arrest were more likely to be depressed (18.8% vs. 9.0%), to smoke (37.0% vs. 21.8%) and to abuse alcohol (16.9% vs. 7.1%), according to the NIS data.

While these findings are based on cardiac arrests brought to a hospital, some opioid-induced cardiac arrests never result in hospital admission, according to data included in a recently issued scientific statement from the American Heart Association.

Rate of opioid-associated cardiac arrests underestimated

In that statement, which was focused on opioid-associated out-of-hospital cardiac arrests (OA-OHCA), numerous studies were cited to support the conclusion that these events are common and underestimated. One problem is that opioid-induced cardiac arrests are not always accurately differentiated from cardiac arrests induced by use of other substances, such as barbiturates, cocaine, or alcohol.

For this and other reasons, the data are inconsistent. One study based on emergency medical service (EMS) response data concluded that 9% of all out-of-hospital cardiac arrests are opioid associated.

In another study using potentially more accurate autopsy data, 60% of the non–cardiac-associated cardiac arrests were found to occur in individuals with potentially lethal serum concentrations of opioids. As 40% of out-of-hospital cardiac arrests were considered non–cardiac related, this suggested that 15% of all out-of-hospital cardiac arrests are opioid related.

In the NIS data, the incident curves of opioid-related cardiac arrests appeared to be flattening in 2018, the last year of data collection, but there was no indication they were declining.
 

Patterns of opioid-induced cardiac arrests evolving

The patterns of opioid-induced cardiac arrest have changed and are likely to continue to change in response to the evolving opioid epidemic, according to the AHA scientific statement. The authors described three waves of opioid abuse. The first, which was related to the promotion of prescription opioids to treat chronic pain that ultimately led to high rates of opioid addiction, peaked in 2012 when rates of these prescriptions began to fall. At that time a second wave, attributed to patients switching to less expensive nonprescription heroin, was already underway. A third wave, attributed to growth in the use of synthetic opioids, such as fentanyl, began in 2013 and is ongoing, according to data cited in the AHA statement.

Recognizing the role of opioids in rising rates of cardiac arrest is important for promoting strategies of effective treatment and prevention, according to Cameron Dezfulian, MD, medical director of the adult congenital heart disease program at Texas Children’s Hospital, Houston. Dr. Dezfulian was vice chair and leader of the writing committee for the AHA scientific statement on OA-OHCA. He said there are plenty of data to support the need for greater attention to the role of opioids in cardiac arrest.

“The recent data affirms the trends many of us have observed without our emergency rooms and ICUs: a steady increase in the proportion of OA-OHCA, primarily in young and otherwise healthy individuals,” he said.

He calls not only for more awareness at the front lines of health are but also for a more comprehensive approach.

“Public health policies and community- and hospital-based interventions are needed to reduce the mortality due to OA-OHCA, which is distinct from the traditional cardiac etiology,” Dr. Dezfulian said.

In opioid-induced cardiac arrest, as in other types of cardiac arrest, prompt initiation of cardiopulmonary resuscitation is essential, but early administration of the opioid antagonist naloxone can also be lifesaving, according to treatment strategies outlined in the AHA scientific statement. The fact that OA-OHCA typically occur in patients with structurally and electrophysiologically normal hearts is emphasized in the AHA statement. So is the enormous public health toll of OA-OHCA.

Death due to opioid overdose, which includes cardiac arrests, is now the leading cause of mortality in the U.S. among individuals between the ages of 25 and 64 years, according to the statement.

Ms. Malik reports no potential conflicts of interest. Dr. Dezfulian reports a financial relationship with Mallinckrodt.

Orthopedic researchers from New York University have proposed standardizing prescribing patterns for patients after fracture surgery so as to include low-dose opioids.

In a paper presented at the annual meeting of the American Academy of Orthopaedic Surgeons, researchers from NYU reported on the implementation of their multimodal strategy, dubbed the “lopioid protocol.”

According to the 2019 National Survey on Drug Use and Health, orthopedic surgeons are the third-highest opioid prescribers in the United States.

Kennneth A. Egol, MD, vice chair of the department of orthopedic surgery at NYU, who is the first author of the study, was motivated to help create the protocol following misconceptions that orthopedic surgeons were helping to fuel the opioid epidemic.

Dr. Egol pointed to the year 1995, when pain became the fifth vital sign after body temperature, pulse rate, respiratory rate, and blood pressure.

Since then, in light of the opioid epidemic, the focus of physicians has shifted away from prescribing strong pain medication and reducing pain scores to zero to instead reducing pain to a manageable level.

Reducing opioid prescriptions can be challenging when patients are prescribed an anti-inflammatory and they subsequently ask their physician for a “pain pill.” Patients sometimes don’t understand that inflammation is what causes pain.

It can also be difficult to convince patients that medications that they can buy over the counter can adequately control their pain, as confirmed in numerous studies.

Multimodal pain therapy aims to reduce the need for opioids by supplementing their use with other oral medications and, at times, long-lasting regional nerve blocks.

Anti-inflammatories act at the site of injury or surgery where inflammation is occurring. Nerves then carry the pain signal to the brain. These signals can be dampened by medications such as gabapentin that act on the nerves themselves. The pain signal is received in the brain, where opioids act by binding to receptors in the brain.

The so-called lopioid protocol does not eliminate opioids completely but rather uses “safer” opioids, such as tramadol, in lieu of stronger narcotics.

The protocol began at NYU on Jan. 1, 2019. It consists in the prescribing of tramadol, meloxicam, gabapentin, and acetaminophen.

The study presented at the AAOS meeting demonstrated statistically significant reductions in visual analogue pain scores at discharge and subsequent medication refills for the 931 patients in the lopioid group, compared with a group of 848 patients who received narcotic prescriptions containing oxycodone from the year prior to the protocol initiation.

Educating patients on the rationale for the prescription combination can help to allay their fears. Dr. Egol thinks it’s important for physicians to explain the dangers of opioids to patients. He said in an interview that he also believes surgeons need to “give [patients] an understanding of why we are pursuing these protocols. They also need to know we will not ignore their pain and concerns.”

Brannon Orton, MD, is an orthopedic surgeon at Confluence Health, in Moses Lake, Wash. He sees a large number of trauma patients and thinks NYU is doing a good job of addressing a difficult problem in orthopedics – especially in the field of trauma.

He said in an interview: “Managing narcotics postoperatively can be challenging due to the fact that many people come into these fractures with a history of narcotic use.” Not only are they used to turning to opioids for pain relief, but they also may have built up a tolerance to them.

Although he hasn’t been using the lopioid protocol specifically, he has been following a multimodal approach regarding the postoperative use of narcotics. Of the study by Dr. Egol and colleagues, he said, “I think their paper presents an effective way of decreasing use of oral narcotics and still adequately managing patients’ pain postoperatively.” Dr. Orton’s own practice utilizes tramadol, acetaminophen, and ibuprofen after fracture surgery.

From Dr. Orton’s perspective, a significant challenge in implementing the lopioid protocol in practice is simply sticking to the plan. “It can become difficult when patients are pressuring staff or physicians for more narcotics. However, I feel that if everybody is on the same page with the plan, then it can be very doable.”

Dr. Egol and NYU try to limit narcotic prescriptions beginning with the patient’s initial visit to the ED. The ED physicians at his institution only “prescribe small amounts of narcotics. Our ED people really limit the amount of opioids prescribed.”

Dr. Egol recommends that all practitioners begin with nonnarcotic medication, even if treating a fracture nonoperatively. “Start low and go higher. I always try to start with NSAIDs and Tylenol,” he said.

Dr. Egol and Dr. Orton reported no relevant financial disclosures.

A version of this article first appeared on Medscape.com.

Orthopedic researchers from New York University have proposed standardizing prescribing patterns for patients after fracture surgery so as to include low-dose opioids.

In a paper presented at the annual meeting of the American Academy of Orthopaedic Surgeons, researchers from NYU reported on the implementation of their multimodal strategy, dubbed the “lopioid protocol.”

According to the 2019 National Survey on Drug Use and Health, orthopedic surgeons are the third-highest opioid prescribers in the United States.

Kennneth A. Egol, MD, vice chair of the department of orthopedic surgery at NYU, who is the first author of the study, was motivated to help create the protocol following misconceptions that orthopedic surgeons were helping to fuel the opioid epidemic.

Dr. Egol pointed to the year 1995, when pain became the fifth vital sign after body temperature, pulse rate, respiratory rate, and blood pressure.

Since then, in light of the opioid epidemic, the focus of physicians has shifted away from prescribing strong pain medication and reducing pain scores to zero to instead reducing pain to a manageable level.

Reducing opioid prescriptions can be challenging when patients are prescribed an anti-inflammatory and they subsequently ask their physician for a “pain pill.” Patients sometimes don’t understand that inflammation is what causes pain.

It can also be difficult to convince patients that medications that they can buy over the counter can adequately control their pain, as confirmed in numerous studies.

Multimodal pain therapy aims to reduce the need for opioids by supplementing their use with other oral medications and, at times, long-lasting regional nerve blocks.

Anti-inflammatories act at the site of injury or surgery where inflammation is occurring. Nerves then carry the pain signal to the brain. These signals can be dampened by medications such as gabapentin that act on the nerves themselves. The pain signal is received in the brain, where opioids act by binding to receptors in the brain.

The so-called lopioid protocol does not eliminate opioids completely but rather uses “safer” opioids, such as tramadol, in lieu of stronger narcotics.

The protocol began at NYU on Jan. 1, 2019. It consists in the prescribing of tramadol, meloxicam, gabapentin, and acetaminophen.

The study presented at the AAOS meeting demonstrated statistically significant reductions in visual analogue pain scores at discharge and subsequent medication refills for the 931 patients in the lopioid group, compared with a group of 848 patients who received narcotic prescriptions containing oxycodone from the year prior to the protocol initiation.

Educating patients on the rationale for the prescription combination can help to allay their fears. Dr. Egol thinks it’s important for physicians to explain the dangers of opioids to patients. He said in an interview that he also believes surgeons need to “give [patients] an understanding of why we are pursuing these protocols. They also need to know we will not ignore their pain and concerns.”

Brannon Orton, MD, is an orthopedic surgeon at Confluence Health, in Moses Lake, Wash. He sees a large number of trauma patients and thinks NYU is doing a good job of addressing a difficult problem in orthopedics – especially in the field of trauma.

He said in an interview: “Managing narcotics postoperatively can be challenging due to the fact that many people come into these fractures with a history of narcotic use.” Not only are they used to turning to opioids for pain relief, but they also may have built up a tolerance to them.

Although he hasn’t been using the lopioid protocol specifically, he has been following a multimodal approach regarding the postoperative use of narcotics. Of the study by Dr. Egol and colleagues, he said, “I think their paper presents an effective way of decreasing use of oral narcotics and still adequately managing patients’ pain postoperatively.” Dr. Orton’s own practice utilizes tramadol, acetaminophen, and ibuprofen after fracture surgery.

From Dr. Orton’s perspective, a significant challenge in implementing the lopioid protocol in practice is simply sticking to the plan. “It can become difficult when patients are pressuring staff or physicians for more narcotics. However, I feel that if everybody is on the same page with the plan, then it can be very doable.”

Dr. Egol and NYU try to limit narcotic prescriptions beginning with the patient’s initial visit to the ED. The ED physicians at his institution only “prescribe small amounts of narcotics. Our ED people really limit the amount of opioids prescribed.”

Dr. Egol recommends that all practitioners begin with nonnarcotic medication, even if treating a fracture nonoperatively. “Start low and go higher. I always try to start with NSAIDs and Tylenol,” he said.

Dr. Egol and Dr. Orton reported no relevant financial disclosures.

A version of this article first appeared on Medscape.com.

Orthopedic researchers from New York University have proposed standardizing prescribing patterns for patients after fracture surgery so as to include low-dose opioids.

In a paper presented at the annual meeting of the American Academy of Orthopaedic Surgeons, researchers from NYU reported on the implementation of their multimodal strategy, dubbed the “lopioid protocol.”

According to the 2019 National Survey on Drug Use and Health, orthopedic surgeons are the third-highest opioid prescribers in the United States.

Kennneth A. Egol, MD, vice chair of the department of orthopedic surgery at NYU, who is the first author of the study, was motivated to help create the protocol following misconceptions that orthopedic surgeons were helping to fuel the opioid epidemic.

Dr. Egol pointed to the year 1995, when pain became the fifth vital sign after body temperature, pulse rate, respiratory rate, and blood pressure.

Since then, in light of the opioid epidemic, the focus of physicians has shifted away from prescribing strong pain medication and reducing pain scores to zero to instead reducing pain to a manageable level.

Reducing opioid prescriptions can be challenging when patients are prescribed an anti-inflammatory and they subsequently ask their physician for a “pain pill.” Patients sometimes don’t understand that inflammation is what causes pain.

It can also be difficult to convince patients that medications that they can buy over the counter can adequately control their pain, as confirmed in numerous studies.

Multimodal pain therapy aims to reduce the need for opioids by supplementing their use with other oral medications and, at times, long-lasting regional nerve blocks.

Anti-inflammatories act at the site of injury or surgery where inflammation is occurring. Nerves then carry the pain signal to the brain. These signals can be dampened by medications such as gabapentin that act on the nerves themselves. The pain signal is received in the brain, where opioids act by binding to receptors in the brain.

The so-called lopioid protocol does not eliminate opioids completely but rather uses “safer” opioids, such as tramadol, in lieu of stronger narcotics.

The protocol began at NYU on Jan. 1, 2019. It consists in the prescribing of tramadol, meloxicam, gabapentin, and acetaminophen.

The study presented at the AAOS meeting demonstrated statistically significant reductions in visual analogue pain scores at discharge and subsequent medication refills for the 931 patients in the lopioid group, compared with a group of 848 patients who received narcotic prescriptions containing oxycodone from the year prior to the protocol initiation.

Educating patients on the rationale for the prescription combination can help to allay their fears. Dr. Egol thinks it’s important for physicians to explain the dangers of opioids to patients. He said in an interview that he also believes surgeons need to “give [patients] an understanding of why we are pursuing these protocols. They also need to know we will not ignore their pain and concerns.”

Brannon Orton, MD, is an orthopedic surgeon at Confluence Health, in Moses Lake, Wash. He sees a large number of trauma patients and thinks NYU is doing a good job of addressing a difficult problem in orthopedics – especially in the field of trauma.

He said in an interview: “Managing narcotics postoperatively can be challenging due to the fact that many people come into these fractures with a history of narcotic use.” Not only are they used to turning to opioids for pain relief, but they also may have built up a tolerance to them.

Although he hasn’t been using the lopioid protocol specifically, he has been following a multimodal approach regarding the postoperative use of narcotics. Of the study by Dr. Egol and colleagues, he said, “I think their paper presents an effective way of decreasing use of oral narcotics and still adequately managing patients’ pain postoperatively.” Dr. Orton’s own practice utilizes tramadol, acetaminophen, and ibuprofen after fracture surgery.

From Dr. Orton’s perspective, a significant challenge in implementing the lopioid protocol in practice is simply sticking to the plan. “It can become difficult when patients are pressuring staff or physicians for more narcotics. However, I feel that if everybody is on the same page with the plan, then it can be very doable.”

Dr. Egol and NYU try to limit narcotic prescriptions beginning with the patient’s initial visit to the ED. The ED physicians at his institution only “prescribe small amounts of narcotics. Our ED people really limit the amount of opioids prescribed.”

Dr. Egol recommends that all practitioners begin with nonnarcotic medication, even if treating a fracture nonoperatively. “Start low and go higher. I always try to start with NSAIDs and Tylenol,” he said.

Dr. Egol and Dr. Orton reported no relevant financial disclosures.

A version of this article first appeared on Medscape.com.

Estimating an individual’s risk of cardiovascular disease (CVD) remains the cornerstone of the 2021 European Society of Cardiology guidelines on CVD prevention in clinical practice. The new guidelines were published online Aug. 30 in the European Heart Journal to coincide with presentation at the European Stroke Congress (ESOC) 2021.   

They were developed by an ESOC task force in collaboration with 12 medical societies and with special contribution of the European Association of Preventive Cardiology.

“A chief goal of the task force was to create a single CVD prevention guideline for everyone – for primary care, for hospital care, for guiding clinical practice – so one guideline for all,” said cochair of the guideline committee Frank Visseren, MD, PhD, University Medical Center Utrecht, Netherlands. “We also wanted to make a more personalized CVD prevention guideline, instead of a one-size-fits-all. In clinical practice, people are very, very different, and we really want to have a more individualized prevention guideline,” said Dr. Visseren, as well as provide “more room for shared decision-making.”
 

Prevention at the individual and population levels

The new guidelines also give more attention to CVD prevention in older persons. “Many of our patients are over 70 years old and we really want to have more detail, more guidance on older persons,” said Dr. Visseren.

The guideline is divided into two sections. One section covers CVD prevention at the individual level in apparently healthy people, in patients with established CVD, and in those with diabetes, familial hypercholesterolemia, or chronic kidney disease.

The other section covers CVD prevention at the population level, including public health policy, interventions, and the environment, including putting in place measures to reduce air pollution, use of fossil fuels, and limiting carbon dioxide emissions.

Targets for blood lipids, blood pressure, and glycemic control in diabetes remain in line with recent ESC guidelines on dyslipidemias, hypertension, or diabetes.

However, the guidelines introduce a new stepwise treatment-intensification approach to achieve these targets, with consideration of CVD risk, treatment benefit of risk factors, risk modifiers, comorbidities, and patient preferences.

The 2021 CVD prevention guidelines also embrace the recently published Systemic Coronary Risk Estimation 2 (SCORE2) and Systemic Coronary Risk Estimation 2-Older Persons (SCORE2-OP) algorithms. “The algorithms we are using are a bit old and we want to have more updated risk prediction, because that’s the starting point of CVD prevention,” Dr. Visseren said.

The guidelines also introduce age-specific risk thresholds for risk factor treatments in apparently healthy people and provide estimation of lifetime CVD risk and treatment benefit. This will allow clinicians to have “an informed discussion with patients on lifetime risk and potential treatment benefits,” Dr. Visseren said.

For the first time, the guidelines recommend smoking cessation regardless of whether it leads to weight gain, as weight gain does not lessen the benefits of cessation.

Regarding exercise, adults of all ages should aim for at least 150-300 minutes a week of moderate, or 75-150 minutes a week of vigorous, aerobic physical activity. The guidelines recommend reducing sedentary time and engaging in at least light activity throughout the day.

Regarding nutrition, the guidelines advise adopting a Mediterranean or similar diet; restricting alcohol intake to a maximum of 100 g per week (a standard drink is 8-14 g); eating fish, preferably fatty fish, at least once a week; and restricting consumption of meat, particularly processed meat.

Also for the first time, the guidelines state that bariatric surgery should be considered for obese individuals at elevated risk of CVD when a healthy diet and exercise fail to lead to weight loss that is maintained.

They note that individuals with mental disorders need additional attention and support to improve adherence to lifestyle changes and drug treatment.

They advise consideration of referring patients with heart disease and significant stress and anxiety to psychotherapeutic stress management to reduce stress symptoms and improve CV outcomes.

Potential cost issues that could be considered when implementing the guidelines are also reviewed.

Dr. Visseren acknowledged and thanked the task force members for continuing their work on the guidelines over the 2 “challenging” years.
 

Setting the bar lower?

Discussant for the guideline presentation, Diederick Grobbee, MD, University Medical Center Utrecht, who was not involved in drafting the guidelines, said he does have one conflict of interest, which is a “passion for prevention.” From that perspective, he said the guideline panel “should be applauded; the once-every-5-year issuing of the prevention guidelines is a major event.”

Dr. Grobbee noted that the working group “really tried to follow their ambitions and goals, in a way making the guidelines simpler, or perhaps setting the bar not initially as high as we used to do, which may, in fact, sometimes scare off physicians and patients alike.”

“We’ve had prevention guidelines for quite some time now, yet looking at what is accomplished in practice is sobering,” said Dr. Grobbee. Introducing a stepwise approach is “really appealing,” he added.

A version of this article first appeared on Medscape.com.

Estimating an individual’s risk of cardiovascular disease (CVD) remains the cornerstone of the 2021 European Society of Cardiology guidelines on CVD prevention in clinical practice. The new guidelines were published online Aug. 30 in the European Heart Journal to coincide with presentation at the European Stroke Congress (ESOC) 2021.   

They were developed by an ESOC task force in collaboration with 12 medical societies and with special contribution of the European Association of Preventive Cardiology.

“A chief goal of the task force was to create a single CVD prevention guideline for everyone – for primary care, for hospital care, for guiding clinical practice – so one guideline for all,” said cochair of the guideline committee Frank Visseren, MD, PhD, University Medical Center Utrecht, Netherlands. “We also wanted to make a more personalized CVD prevention guideline, instead of a one-size-fits-all. In clinical practice, people are very, very different, and we really want to have a more individualized prevention guideline,” said Dr. Visseren, as well as provide “more room for shared decision-making.”
 

Prevention at the individual and population levels

The new guidelines also give more attention to CVD prevention in older persons. “Many of our patients are over 70 years old and we really want to have more detail, more guidance on older persons,” said Dr. Visseren.

The guideline is divided into two sections. One section covers CVD prevention at the individual level in apparently healthy people, in patients with established CVD, and in those with diabetes, familial hypercholesterolemia, or chronic kidney disease.

The other section covers CVD prevention at the population level, including public health policy, interventions, and the environment, including putting in place measures to reduce air pollution, use of fossil fuels, and limiting carbon dioxide emissions.

Targets for blood lipids, blood pressure, and glycemic control in diabetes remain in line with recent ESC guidelines on dyslipidemias, hypertension, or diabetes.

However, the guidelines introduce a new stepwise treatment-intensification approach to achieve these targets, with consideration of CVD risk, treatment benefit of risk factors, risk modifiers, comorbidities, and patient preferences.

The 2021 CVD prevention guidelines also embrace the recently published Systemic Coronary Risk Estimation 2 (SCORE2) and Systemic Coronary Risk Estimation 2-Older Persons (SCORE2-OP) algorithms. “The algorithms we are using are a bit old and we want to have more updated risk prediction, because that’s the starting point of CVD prevention,” Dr. Visseren said.

The guidelines also introduce age-specific risk thresholds for risk factor treatments in apparently healthy people and provide estimation of lifetime CVD risk and treatment benefit. This will allow clinicians to have “an informed discussion with patients on lifetime risk and potential treatment benefits,” Dr. Visseren said.

For the first time, the guidelines recommend smoking cessation regardless of whether it leads to weight gain, as weight gain does not lessen the benefits of cessation.

Regarding exercise, adults of all ages should aim for at least 150-300 minutes a week of moderate, or 75-150 minutes a week of vigorous, aerobic physical activity. The guidelines recommend reducing sedentary time and engaging in at least light activity throughout the day.

Regarding nutrition, the guidelines advise adopting a Mediterranean or similar diet; restricting alcohol intake to a maximum of 100 g per week (a standard drink is 8-14 g); eating fish, preferably fatty fish, at least once a week; and restricting consumption of meat, particularly processed meat.

Also for the first time, the guidelines state that bariatric surgery should be considered for obese individuals at elevated risk of CVD when a healthy diet and exercise fail to lead to weight loss that is maintained.

They note that individuals with mental disorders need additional attention and support to improve adherence to lifestyle changes and drug treatment.

They advise consideration of referring patients with heart disease and significant stress and anxiety to psychotherapeutic stress management to reduce stress symptoms and improve CV outcomes.

Potential cost issues that could be considered when implementing the guidelines are also reviewed.

Dr. Visseren acknowledged and thanked the task force members for continuing their work on the guidelines over the 2 “challenging” years.
 

Setting the bar lower?

Discussant for the guideline presentation, Diederick Grobbee, MD, University Medical Center Utrecht, who was not involved in drafting the guidelines, said he does have one conflict of interest, which is a “passion for prevention.” From that perspective, he said the guideline panel “should be applauded; the once-every-5-year issuing of the prevention guidelines is a major event.”

Dr. Grobbee noted that the working group “really tried to follow their ambitions and goals, in a way making the guidelines simpler, or perhaps setting the bar not initially as high as we used to do, which may, in fact, sometimes scare off physicians and patients alike.”

“We’ve had prevention guidelines for quite some time now, yet looking at what is accomplished in practice is sobering,” said Dr. Grobbee. Introducing a stepwise approach is “really appealing,” he added.

A version of this article first appeared on Medscape.com.

Estimating an individual’s risk of cardiovascular disease (CVD) remains the cornerstone of the 2021 European Society of Cardiology guidelines on CVD prevention in clinical practice. The new guidelines were published online Aug. 30 in the European Heart Journal to coincide with presentation at the European Stroke Congress (ESOC) 2021.   

They were developed by an ESOC task force in collaboration with 12 medical societies and with special contribution of the European Association of Preventive Cardiology.

“A chief goal of the task force was to create a single CVD prevention guideline for everyone – for primary care, for hospital care, for guiding clinical practice – so one guideline for all,” said cochair of the guideline committee Frank Visseren, MD, PhD, University Medical Center Utrecht, Netherlands. “We also wanted to make a more personalized CVD prevention guideline, instead of a one-size-fits-all. In clinical practice, people are very, very different, and we really want to have a more individualized prevention guideline,” said Dr. Visseren, as well as provide “more room for shared decision-making.”
 

Prevention at the individual and population levels

The new guidelines also give more attention to CVD prevention in older persons. “Many of our patients are over 70 years old and we really want to have more detail, more guidance on older persons,” said Dr. Visseren.

The guideline is divided into two sections. One section covers CVD prevention at the individual level in apparently healthy people, in patients with established CVD, and in those with diabetes, familial hypercholesterolemia, or chronic kidney disease.

The other section covers CVD prevention at the population level, including public health policy, interventions, and the environment, including putting in place measures to reduce air pollution, use of fossil fuels, and limiting carbon dioxide emissions.

Targets for blood lipids, blood pressure, and glycemic control in diabetes remain in line with recent ESC guidelines on dyslipidemias, hypertension, or diabetes.

However, the guidelines introduce a new stepwise treatment-intensification approach to achieve these targets, with consideration of CVD risk, treatment benefit of risk factors, risk modifiers, comorbidities, and patient preferences.

The 2021 CVD prevention guidelines also embrace the recently published Systemic Coronary Risk Estimation 2 (SCORE2) and Systemic Coronary Risk Estimation 2-Older Persons (SCORE2-OP) algorithms. “The algorithms we are using are a bit old and we want to have more updated risk prediction, because that’s the starting point of CVD prevention,” Dr. Visseren said.

The guidelines also introduce age-specific risk thresholds for risk factor treatments in apparently healthy people and provide estimation of lifetime CVD risk and treatment benefit. This will allow clinicians to have “an informed discussion with patients on lifetime risk and potential treatment benefits,” Dr. Visseren said.

For the first time, the guidelines recommend smoking cessation regardless of whether it leads to weight gain, as weight gain does not lessen the benefits of cessation.

Regarding exercise, adults of all ages should aim for at least 150-300 minutes a week of moderate, or 75-150 minutes a week of vigorous, aerobic physical activity. The guidelines recommend reducing sedentary time and engaging in at least light activity throughout the day.

Regarding nutrition, the guidelines advise adopting a Mediterranean or similar diet; restricting alcohol intake to a maximum of 100 g per week (a standard drink is 8-14 g); eating fish, preferably fatty fish, at least once a week; and restricting consumption of meat, particularly processed meat.

Also for the first time, the guidelines state that bariatric surgery should be considered for obese individuals at elevated risk of CVD when a healthy diet and exercise fail to lead to weight loss that is maintained.

They note that individuals with mental disorders need additional attention and support to improve adherence to lifestyle changes and drug treatment.

They advise consideration of referring patients with heart disease and significant stress and anxiety to psychotherapeutic stress management to reduce stress symptoms and improve CV outcomes.

Potential cost issues that could be considered when implementing the guidelines are also reviewed.

Dr. Visseren acknowledged and thanked the task force members for continuing their work on the guidelines over the 2 “challenging” years.
 

Setting the bar lower?

Discussant for the guideline presentation, Diederick Grobbee, MD, University Medical Center Utrecht, who was not involved in drafting the guidelines, said he does have one conflict of interest, which is a “passion for prevention.” From that perspective, he said the guideline panel “should be applauded; the once-every-5-year issuing of the prevention guidelines is a major event.”

Dr. Grobbee noted that the working group “really tried to follow their ambitions and goals, in a way making the guidelines simpler, or perhaps setting the bar not initially as high as we used to do, which may, in fact, sometimes scare off physicians and patients alike.”

“We’ve had prevention guidelines for quite some time now, yet looking at what is accomplished in practice is sobering,” said Dr. Grobbee. Introducing a stepwise approach is “really appealing,” he added.

A version of this article first appeared on Medscape.com.

The brain is inarguably the most complex and mysterious organ in the human body.

As the epicenter of intelligence, mastermind of movement, and song for our senses, the brain is more than a 3-lb organ encased in shell and fluid. Rather, it is the crown jewel that defines the self and, broadly, humanity.

©Thinkstock

For decades now, researchers have been exploring the potential for connecting our own astounding biological “computer” with actual physical mainframes. These so-called “brain-computer interfaces” (BCIs) are showing promise in treating an array of conditions, including paralysis, deafness, stroke, and even psychiatric disorders.

Among the big players in this area of research is billionaire entrepreneur Elon Musk, who in 2016 founded Neuralink. The company’s short-term mission is to develop a brain-to-machine interface to help people with neurologic conditions (for example, Parkinson’s disease). The long-term mission is to steer humanity into the era of “superhuman cognition.”

But first, some neuroscience 101.

Neurons are specialized cells that transmit and receive information. The basic structure of a neuron includes the dendrite, soma, and axon. The dendrite is the signal receiver. The soma is the cell body that is connected to the dendrites and serves as a structure to pass signals. The axon, also known as the nerve fiber, transmits the signal away from the soma.

Neurons communicate with each other at the synapse (for example, axon-dendrite connection). Neurons send information to each other through action potentials. An action potential may be defined as an electric impulse that transmits down the axon, causing the release of neurotransmitters, which may consequently either inhibit or excite the next neuron (leading to the initiation of another action potential).

So how will the company and other BCI companies tap into this evolutionarily ancient system to develop an implant that will obtain and decode information output from the brain?

The Neuralink implant is composed of three parts: The Link, neural threads, and the charger.

A robotic system, controlled by a neurosurgeon, will place an implant into the brain. The Link is the central component. It processes and transmits neural signals. The micron-scale neural threads are connected to the Link and other areas of the brain. The threads also contain electrodes, which are responsible for detecting neural signals. The charger ensures the battery is charged via wireless connection.

The invasive nature of this implant allows for precise readouts of electric outputs from the brain – unlike noninvasive devices, which are less sensitive and specific. Additionally, owing to its small size, engineers and neurosurgeons can implant the device in very specific brain regions as well as customize electrode distribution.

The Neuralink implant would be paired with an application via Bluetooth connection. The goal is to enable someone with the implant to control their device or computer by simply thinking. The application offers several exercises to help guide and train individuals on how to use the implant for its intended purpose. This technology would allow people with neurologic difficulties (for example, paralysis) to communicate more easily through text or speech synthesis, as well as partake in creative activities such as photography.

Existing text and speech synthesis technology are already underway. For example, Synchron, a BCI platform company, is investigating the use of Stentrode for people with severe paralysis. This neuroprosthesis was designed to help people associate thought with movement through Bluetooth technology (for example, texting, emailing, shopping, online banking). Preliminary results from a study in which the device was used for patients with amyotrophic lateral sclerosis showed improvements in functional independence via direct thinking.

Software intended to enable high-performance handwriting utilizing BCI technology is being developed by Francis R. Willett, PhD, at Stanford (Calif.) University. The technology has also shown promise.

“We’ve learned that the brain retains its ability to prescribe fine movements a full decade after the body has lost its ability to execute those movements,” says Dr. Willett, who recently reported on results from a BCI study of handwriting conversion in an individual with full-body paralysis. Through a recurrent neural networking decoding approach, the BrainGate study participant was able to type 90 characters per minute – with an impressive 94.1% raw accuracy – using thoughts alone.

Although not a fully implantable brain device, this percutaneous implant has also been studied of its capacity to restore arm function among individuals who suffered from chronic stroke. Preliminary results from the Cortimo trials, led by Mijail D. Serruya, MD, an assistant professor at Thomas Jefferson University, Philadelphia, have been positive. Researchers implanted microelectrode arrays to decode brain signals and power motor function in a participant who had experienced a stroke 2 years earlier. The participant was able to use a powered arm brace on their paralyzed arm.

Neuralink recently released a video demonstrating the use of the interface in a monkey named Pager as it played a game with a joystick. Company researchers inserted a 1024-Electrode neural recording and data transmission device called the N1 Link into the left and right motor cortices. Using the implant, neural activity was sent to a decoder algorithm. Throughout the process, the decoder algorithm was refined and calibrated. After a few minutes, Pager was able to control the cursor on the screen using his mind instead of the joystick.

Mr. Musk hopes to develop Neuralink further to change not only the way we treat neurological disorders but also the way we interact with ourselves and our environment. It’s a lofty goal to be sure, but one that doesn’t seem outside the realm of possibility in the near future.
 

Known unknowns: The ethical dilemmas

One major conundrum facing the future of BCI technology is that researchers don’t fully understand the science regarding how brain signaling, artificial intelligence (AI) software, and prostheses interact. Although offloading computations improves the predictive nature of AI algorithms, there are concerns of identity and personal agency.

How do we know that an action is truly the result of one’s own thinking or, rather, the outcome of AI software? In this context, the autocorrect function while typing can be incredibly useful when we’re in a pinch for time, when we’re using one hand to type, or because of ease. However, it’s also easy to create and send out unintended or inappropriate messages.

These algorithms are designed to learn from our behavior and anticipate our next move. However, a question arises as to whether we are the authors of our own thoughts or whether we are simply the device that delivers messages under the control of external forces.

“People may question whether new personality changes they experience are truly representative of themselves or whether they are now a product of the implant (e.g., ‘Is that really me?’; ‘Have I grown as a person, or is it the technology?’). This then raises questions about agency and who we are as people,” says Kerry Bowman, PhD, a clinical bioethicist and assistant professor at the Temerty Faculty of Medicine of the University of Toronto.

It’s important to have safeguards in place to ensure the privacy of our thoughts. In an age where data is currency, it’s crucial to establish boundaries to preserve our autonomy and prevent exploitation (for example, by private companies or hackers). Although Neuralink and BCIs generally are certainly pushing the boundaries of neural engineering in profound ways, it’s important to note the biological and ethical implications of this technology.

As Dr. Bowman points out, “throughout the entire human story, under the worst of human circumstances, such as captivity and torture, the one safe ground and place for all people has been the privacy of one’s own mind. No one could ever interfere, take away, or be aware of those thoughts. However, this technology challenges one’s own privacy – that this technology (and, by extension, a company) could be aware of those thoughts.”

A version of this article first appeared on Medscape.com.

The brain is inarguably the most complex and mysterious organ in the human body.

As the epicenter of intelligence, mastermind of movement, and song for our senses, the brain is more than a 3-lb organ encased in shell and fluid. Rather, it is the crown jewel that defines the self and, broadly, humanity.

©Thinkstock

For decades now, researchers have been exploring the potential for connecting our own astounding biological “computer” with actual physical mainframes. These so-called “brain-computer interfaces” (BCIs) are showing promise in treating an array of conditions, including paralysis, deafness, stroke, and even psychiatric disorders.

Among the big players in this area of research is billionaire entrepreneur Elon Musk, who in 2016 founded Neuralink. The company’s short-term mission is to develop a brain-to-machine interface to help people with neurologic conditions (for example, Parkinson’s disease). The long-term mission is to steer humanity into the era of “superhuman cognition.”

But first, some neuroscience 101.

Neurons are specialized cells that transmit and receive information. The basic structure of a neuron includes the dendrite, soma, and axon. The dendrite is the signal receiver. The soma is the cell body that is connected to the dendrites and serves as a structure to pass signals. The axon, also known as the nerve fiber, transmits the signal away from the soma.

Neurons communicate with each other at the synapse (for example, axon-dendrite connection). Neurons send information to each other through action potentials. An action potential may be defined as an electric impulse that transmits down the axon, causing the release of neurotransmitters, which may consequently either inhibit or excite the next neuron (leading to the initiation of another action potential).

So how will the company and other BCI companies tap into this evolutionarily ancient system to develop an implant that will obtain and decode information output from the brain?

The Neuralink implant is composed of three parts: The Link, neural threads, and the charger.

A robotic system, controlled by a neurosurgeon, will place an implant into the brain. The Link is the central component. It processes and transmits neural signals. The micron-scale neural threads are connected to the Link and other areas of the brain. The threads also contain electrodes, which are responsible for detecting neural signals. The charger ensures the battery is charged via wireless connection.

The invasive nature of this implant allows for precise readouts of electric outputs from the brain – unlike noninvasive devices, which are less sensitive and specific. Additionally, owing to its small size, engineers and neurosurgeons can implant the device in very specific brain regions as well as customize electrode distribution.

The Neuralink implant would be paired with an application via Bluetooth connection. The goal is to enable someone with the implant to control their device or computer by simply thinking. The application offers several exercises to help guide and train individuals on how to use the implant for its intended purpose. This technology would allow people with neurologic difficulties (for example, paralysis) to communicate more easily through text or speech synthesis, as well as partake in creative activities such as photography.

Existing text and speech synthesis technology are already underway. For example, Synchron, a BCI platform company, is investigating the use of Stentrode for people with severe paralysis. This neuroprosthesis was designed to help people associate thought with movement through Bluetooth technology (for example, texting, emailing, shopping, online banking). Preliminary results from a study in which the device was used for patients with amyotrophic lateral sclerosis showed improvements in functional independence via direct thinking.

Software intended to enable high-performance handwriting utilizing BCI technology is being developed by Francis R. Willett, PhD, at Stanford (Calif.) University. The technology has also shown promise.

“We’ve learned that the brain retains its ability to prescribe fine movements a full decade after the body has lost its ability to execute those movements,” says Dr. Willett, who recently reported on results from a BCI study of handwriting conversion in an individual with full-body paralysis. Through a recurrent neural networking decoding approach, the BrainGate study participant was able to type 90 characters per minute – with an impressive 94.1% raw accuracy – using thoughts alone.

Although not a fully implantable brain device, this percutaneous implant has also been studied of its capacity to restore arm function among individuals who suffered from chronic stroke. Preliminary results from the Cortimo trials, led by Mijail D. Serruya, MD, an assistant professor at Thomas Jefferson University, Philadelphia, have been positive. Researchers implanted microelectrode arrays to decode brain signals and power motor function in a participant who had experienced a stroke 2 years earlier. The participant was able to use a powered arm brace on their paralyzed arm.

Neuralink recently released a video demonstrating the use of the interface in a monkey named Pager as it played a game with a joystick. Company researchers inserted a 1024-Electrode neural recording and data transmission device called the N1 Link into the left and right motor cortices. Using the implant, neural activity was sent to a decoder algorithm. Throughout the process, the decoder algorithm was refined and calibrated. After a few minutes, Pager was able to control the cursor on the screen using his mind instead of the joystick.

Mr. Musk hopes to develop Neuralink further to change not only the way we treat neurological disorders but also the way we interact with ourselves and our environment. It’s a lofty goal to be sure, but one that doesn’t seem outside the realm of possibility in the near future.
 

Known unknowns: The ethical dilemmas

One major conundrum facing the future of BCI technology is that researchers don’t fully understand the science regarding how brain signaling, artificial intelligence (AI) software, and prostheses interact. Although offloading computations improves the predictive nature of AI algorithms, there are concerns of identity and personal agency.

How do we know that an action is truly the result of one’s own thinking or, rather, the outcome of AI software? In this context, the autocorrect function while typing can be incredibly useful when we’re in a pinch for time, when we’re using one hand to type, or because of ease. However, it’s also easy to create and send out unintended or inappropriate messages.

These algorithms are designed to learn from our behavior and anticipate our next move. However, a question arises as to whether we are the authors of our own thoughts or whether we are simply the device that delivers messages under the control of external forces.

“People may question whether new personality changes they experience are truly representative of themselves or whether they are now a product of the implant (e.g., ‘Is that really me?’; ‘Have I grown as a person, or is it the technology?’). This then raises questions about agency and who we are as people,” says Kerry Bowman, PhD, a clinical bioethicist and assistant professor at the Temerty Faculty of Medicine of the University of Toronto.

It’s important to have safeguards in place to ensure the privacy of our thoughts. In an age where data is currency, it’s crucial to establish boundaries to preserve our autonomy and prevent exploitation (for example, by private companies or hackers). Although Neuralink and BCIs generally are certainly pushing the boundaries of neural engineering in profound ways, it’s important to note the biological and ethical implications of this technology.

As Dr. Bowman points out, “throughout the entire human story, under the worst of human circumstances, such as captivity and torture, the one safe ground and place for all people has been the privacy of one’s own mind. No one could ever interfere, take away, or be aware of those thoughts. However, this technology challenges one’s own privacy – that this technology (and, by extension, a company) could be aware of those thoughts.”

A version of this article first appeared on Medscape.com.

The brain is inarguably the most complex and mysterious organ in the human body.

As the epicenter of intelligence, mastermind of movement, and song for our senses, the brain is more than a 3-lb organ encased in shell and fluid. Rather, it is the crown jewel that defines the self and, broadly, humanity.

©Thinkstock

For decades now, researchers have been exploring the potential for connecting our own astounding biological “computer” with actual physical mainframes. These so-called “brain-computer interfaces” (BCIs) are showing promise in treating an array of conditions, including paralysis, deafness, stroke, and even psychiatric disorders.

Among the big players in this area of research is billionaire entrepreneur Elon Musk, who in 2016 founded Neuralink. The company’s short-term mission is to develop a brain-to-machine interface to help people with neurologic conditions (for example, Parkinson’s disease). The long-term mission is to steer humanity into the era of “superhuman cognition.”

But first, some neuroscience 101.

Neurons are specialized cells that transmit and receive information. The basic structure of a neuron includes the dendrite, soma, and axon. The dendrite is the signal receiver. The soma is the cell body that is connected to the dendrites and serves as a structure to pass signals. The axon, also known as the nerve fiber, transmits the signal away from the soma.

Neurons communicate with each other at the synapse (for example, axon-dendrite connection). Neurons send information to each other through action potentials. An action potential may be defined as an electric impulse that transmits down the axon, causing the release of neurotransmitters, which may consequently either inhibit or excite the next neuron (leading to the initiation of another action potential).

So how will the company and other BCI companies tap into this evolutionarily ancient system to develop an implant that will obtain and decode information output from the brain?

The Neuralink implant is composed of three parts: The Link, neural threads, and the charger.

A robotic system, controlled by a neurosurgeon, will place an implant into the brain. The Link is the central component. It processes and transmits neural signals. The micron-scale neural threads are connected to the Link and other areas of the brain. The threads also contain electrodes, which are responsible for detecting neural signals. The charger ensures the battery is charged via wireless connection.

The invasive nature of this implant allows for precise readouts of electric outputs from the brain – unlike noninvasive devices, which are less sensitive and specific. Additionally, owing to its small size, engineers and neurosurgeons can implant the device in very specific brain regions as well as customize electrode distribution.

The Neuralink implant would be paired with an application via Bluetooth connection. The goal is to enable someone with the implant to control their device or computer by simply thinking. The application offers several exercises to help guide and train individuals on how to use the implant for its intended purpose. This technology would allow people with neurologic difficulties (for example, paralysis) to communicate more easily through text or speech synthesis, as well as partake in creative activities such as photography.

Existing text and speech synthesis technology are already underway. For example, Synchron, a BCI platform company, is investigating the use of Stentrode for people with severe paralysis. This neuroprosthesis was designed to help people associate thought with movement through Bluetooth technology (for example, texting, emailing, shopping, online banking). Preliminary results from a study in which the device was used for patients with amyotrophic lateral sclerosis showed improvements in functional independence via direct thinking.

Software intended to enable high-performance handwriting utilizing BCI technology is being developed by Francis R. Willett, PhD, at Stanford (Calif.) University. The technology has also shown promise.

“We’ve learned that the brain retains its ability to prescribe fine movements a full decade after the body has lost its ability to execute those movements,” says Dr. Willett, who recently reported on results from a BCI study of handwriting conversion in an individual with full-body paralysis. Through a recurrent neural networking decoding approach, the BrainGate study participant was able to type 90 characters per minute – with an impressive 94.1% raw accuracy – using thoughts alone.

Although not a fully implantable brain device, this percutaneous implant has also been studied of its capacity to restore arm function among individuals who suffered from chronic stroke. Preliminary results from the Cortimo trials, led by Mijail D. Serruya, MD, an assistant professor at Thomas Jefferson University, Philadelphia, have been positive. Researchers implanted microelectrode arrays to decode brain signals and power motor function in a participant who had experienced a stroke 2 years earlier. The participant was able to use a powered arm brace on their paralyzed arm.

Neuralink recently released a video demonstrating the use of the interface in a monkey named Pager as it played a game with a joystick. Company researchers inserted a 1024-Electrode neural recording and data transmission device called the N1 Link into the left and right motor cortices. Using the implant, neural activity was sent to a decoder algorithm. Throughout the process, the decoder algorithm was refined and calibrated. After a few minutes, Pager was able to control the cursor on the screen using his mind instead of the joystick.

Mr. Musk hopes to develop Neuralink further to change not only the way we treat neurological disorders but also the way we interact with ourselves and our environment. It’s a lofty goal to be sure, but one that doesn’t seem outside the realm of possibility in the near future.
 

Known unknowns: The ethical dilemmas

One major conundrum facing the future of BCI technology is that researchers don’t fully understand the science regarding how brain signaling, artificial intelligence (AI) software, and prostheses interact. Although offloading computations improves the predictive nature of AI algorithms, there are concerns of identity and personal agency.

How do we know that an action is truly the result of one’s own thinking or, rather, the outcome of AI software? In this context, the autocorrect function while typing can be incredibly useful when we’re in a pinch for time, when we’re using one hand to type, or because of ease. However, it’s also easy to create and send out unintended or inappropriate messages.

These algorithms are designed to learn from our behavior and anticipate our next move. However, a question arises as to whether we are the authors of our own thoughts or whether we are simply the device that delivers messages under the control of external forces.

“People may question whether new personality changes they experience are truly representative of themselves or whether they are now a product of the implant (e.g., ‘Is that really me?’; ‘Have I grown as a person, or is it the technology?’). This then raises questions about agency and who we are as people,” says Kerry Bowman, PhD, a clinical bioethicist and assistant professor at the Temerty Faculty of Medicine of the University of Toronto.

It’s important to have safeguards in place to ensure the privacy of our thoughts. In an age where data is currency, it’s crucial to establish boundaries to preserve our autonomy and prevent exploitation (for example, by private companies or hackers). Although Neuralink and BCIs generally are certainly pushing the boundaries of neural engineering in profound ways, it’s important to note the biological and ethical implications of this technology.

As Dr. Bowman points out, “throughout the entire human story, under the worst of human circumstances, such as captivity and torture, the one safe ground and place for all people has been the privacy of one’s own mind. No one could ever interfere, take away, or be aware of those thoughts. However, this technology challenges one’s own privacy – that this technology (and, by extension, a company) could be aware of those thoughts.”

A version of this article first appeared on Medscape.com.

Background: Falls are the leading cause of unintentional injuries and injury-related deaths among adults aged 65 years and older. FRIDs (such as antidepressants, sedatives-hypnotics, and opioids) continue to be a major contributor for risk of falls. At the same time, little is known about prevalence of use or interventions directed toward reduction of use in older adults presenting with fall.

Limitations of this review included high risk of bias in observational studies and unclear timeline definitions of interventions or outcome measurements in the intervention studies. In conclusion, there is a significant need for well-designed interventions targeted at reducing FRID use in conjunction with other risk factors to decrease the incidence of falls comprehensively. An aggressive approach directed toward patient education along with primary care communication may be the key to reducing FRID use in this population.

Bottom line: With limited evidence, there is a high prevalence of FRID use in older adults presenting with falls and no reduction in FRID use following the encounter.

Citation: Hart LA et al. Use of fall risk-increasing drugs around a fall-related injury in older adults: A systematic review. J Am Geriatr Soc. 2020 Feb 17. doi: 10.1111/jgs.16369.

Dr. Yarra is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: Falls are the leading cause of unintentional injuries and injury-related deaths among adults aged 65 years and older. FRIDs (such as antidepressants, sedatives-hypnotics, and opioids) continue to be a major contributor for risk of falls. At the same time, little is known about prevalence of use or interventions directed toward reduction of use in older adults presenting with fall.

Limitations of this review included high risk of bias in observational studies and unclear timeline definitions of interventions or outcome measurements in the intervention studies. In conclusion, there is a significant need for well-designed interventions targeted at reducing FRID use in conjunction with other risk factors to decrease the incidence of falls comprehensively. An aggressive approach directed toward patient education along with primary care communication may be the key to reducing FRID use in this population.

Bottom line: With limited evidence, there is a high prevalence of FRID use in older adults presenting with falls and no reduction in FRID use following the encounter.

Citation: Hart LA et al. Use of fall risk-increasing drugs around a fall-related injury in older adults: A systematic review. J Am Geriatr Soc. 2020 Feb 17. doi: 10.1111/jgs.16369.

Dr. Yarra is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

Background: Falls are the leading cause of unintentional injuries and injury-related deaths among adults aged 65 years and older. FRIDs (such as antidepressants, sedatives-hypnotics, and opioids) continue to be a major contributor for risk of falls. At the same time, little is known about prevalence of use or interventions directed toward reduction of use in older adults presenting with fall.

Limitations of this review included high risk of bias in observational studies and unclear timeline definitions of interventions or outcome measurements in the intervention studies. In conclusion, there is a significant need for well-designed interventions targeted at reducing FRID use in conjunction with other risk factors to decrease the incidence of falls comprehensively. An aggressive approach directed toward patient education along with primary care communication may be the key to reducing FRID use in this population.

Bottom line: With limited evidence, there is a high prevalence of FRID use in older adults presenting with falls and no reduction in FRID use following the encounter.

Citation: Hart LA et al. Use of fall risk-increasing drugs around a fall-related injury in older adults: A systematic review. J Am Geriatr Soc. 2020 Feb 17. doi: 10.1111/jgs.16369.

Dr. Yarra is a hospitalist and assistant professor of medicine at UK HealthCare, Lexington, Ky.

People with multiple sclerosis (MS) and depression have an increased risk of death, compared with those with one or neither condition, as well as an increased risk of vascular disease, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.

The study was published in Neurology.

To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.

People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.

As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
 

Does treating depression decrease the likelihood of vascular disease?

“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?

“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?

“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
 

Evaluating the biological interaction between MS and depression

Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.

“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.

“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.

Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.

In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”

Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.

People with multiple sclerosis (MS) and depression have an increased risk of death, compared with those with one or neither condition, as well as an increased risk of vascular disease, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.

The study was published in Neurology.

To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.

People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.

As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
 

Does treating depression decrease the likelihood of vascular disease?

“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?

“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?

“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
 

Evaluating the biological interaction between MS and depression

Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.

“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.

“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.

Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.

In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”

Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.

People with multiple sclerosis (MS) and depression have an increased risk of death, compared with those with one or neither condition, as well as an increased risk of vascular disease, a new study has found. “The effects of depression and MS on all-cause mortality are synergistic,” wrote lead author Raffaele Palladino, MD, PhD, research associate, faculty of medicine, Imperial College London.

The study was published in Neurology.

To assess the association between depression, vascular disease, and death in patients with MS, the researchers launched a population-based retrospective cohort study that reviewed English medical records from January 1987 to December 2018 and matched people with and without MS. Ultimately, 12,251 people with MS were matched with 72,572 controls. At baseline, 21% of the MS group (n = 2,535) and 9% of the controls (n = 6,278) had depression. Women were the majority in both cohorts and were more likely than men to be depressed.

People with both MS and depression had an all-cause mortality rate of 10.3 cases per 100,000 person-years (95% confidence interval, 9.17-11.57), compared with 10.6 for people with MS without depression (95% CI, 9.99-11.21), 3.6 for people with depression but not MS (95% CI, 3.18-4.05), and 2.5 for people with neither condition (95% CI, 2.42-2.64). Compared with controls without depression, the 10-year hazard of all-cause mortality was increasingly greater in controls with depression (hazard ratio, 1.75; 95% CI, 1.59-1.91), people with MS but not depression (HR, 3.88; 95% CI, 3.66-4.10), and people with MS and depression (HR, 5.43; 95% CI, 4.88-5.96). Overall, 14% of the observed effect on mortality was attributable to the interaction between MS status and depression.

As for vascular diseases, people with MS had an increased risk regardless of their depression status. That said, people with MS and depression (HR, 3.30; 95% CI, 2.37-4.23) had a notably higher risk than people with MS and no depression (HR, 1.48; 95% CI, 1.23-1.74). Women with MS and depression also had a greater risk of vascular disease than women with MS and no depression, while men with MS did not have significantly different risks of acute coronary syndrome or composite macrovascular disease than those in the control group who did not suffer from depression.
 

Does treating depression decrease the likelihood of vascular disease?

“The take-home message for me is the importance of treating depression in this population, in which we see it with great regularity,” Joseph Berger, MD, professor of neurology and associate chief of the multiple sclerosis division at the University of Pennsylvania, Philadelphia, said in an interview. “The question that I have is: If you treat depression in an individual with MS or an individual who is simply depressed and thus at risk for the subsequent development of vascular disease, does it decrease the likelihood of their subsequent development of vascular disease in comparison to had you not?

“I presume it does,” he added, noting that “the theories underlying why depression would increase one’s risk of subsequent vascular disease are enumerated by the authors, including such things as increased inflammation. Now, the inflammation may be contributing to the depression, or the depression may be contributing to the inflammation; it may be one of those chicken-and-egg scenarios. But if you decrease the depression, do you thereby decrease the inflammation, which has a pernicious effect on endothelial cells and increases one’s vascular risk?

“Alternatively, lifestyle in depressed patients is also altered,” he said. “They’re far less likely to engage in exercise, healthy habits, and healthy diets, and more likely perhaps to smoke. These all need to be addressed, but this study certainly gives you a greater impetus as a MS neurologist to address the issue of depression, realizing that there is also this comorbidity of vascular disease.”
 

Evaluating the biological interaction between MS and depression

Based on this and other studies, the joint effect of MS and depression on all-cause mortality may qualify as a biological interaction, Amber Salter, PhD, of the University of Texas Southwestern Medical Center, Dallas, wrote in an accompanying editorial.

“Biological interactions consider whether the joint effect of two factors follow an additive pattern, or the joint effect of two factors is greater than the sum of the individual effects for each factor alone,” she wrote. And though the interaction was not found to be present for vascular disease and cardiovascular mortality, it was for all-cause mortality.

“When warranted, the evaluation of biological interactions in future studies should be considered to provide insight on target subpopulations for interventions or test for potential mechanistic forms of interaction,” she added.

Dr. Salter highlighted the study’s strengths, including a large sample size and six controls matched to each MS patient. She also stated that the researchers’ inability to control for risk factors like body mass index and physical activity means the 14% increase in mortality “may not be a large absolute increase in mortality when other covariates cannot be considered.” In addition, their lack of data on suicide – and its association with depression – offers up the possibility that increases in mortality could be tied to a “potentially modifiable risk” as opposed to a biologically increased one.

In acknowledging their study’s limitations, the authors stated that body mass index, though an important vascular risk factor, has a “modest” association with mortality, and that the average annual suicide rate in the MS population – though higher than in the non-MS population – is still “relatively low.”

Two of the authors disclosed receiving support, including grants and research funding, from various institutions and organizations in the United Kingdom, the United States, and Canada, as well as several pharmaceutical companies. Dr. Salter reported no relevant disclosures.

Opioid overdose deaths were significantly higher during 2020, but occurrences were not homogeneous across nine states. Male deaths were higher than in the 2 previous years in two states, according to a new, granular examination of data collected by researchers at the Massachusetts General Hospital (Mass General), Boston.

The analysis also showed that synthetic opioids such as fentanyl played an outsized role in most of the states that were reviewed. Additional drugs of abuse found in decedents, such as cocaine and psychostimulants, were more prevalent in some states than in others.

The Centers for Disease Control and Prevention used provisional death data in its recent report. It found that opioid-related deaths substantially rose in 2020 and that synthetic opioids were a primary driver.

The current Mass General analysis provides a more timely and detailed dive, senior author Mohammad Jalali, PhD, who is a senior scientist at Mass General’s Institute for Technology Assessment, told this news organization.

The findings, which have not yet been peer reviewed, were published in MedRxiv.
 

Shifting sands of opioid use disorder

Dr. Jalali and colleagues used a decision analysis approach to study opioid data in the hopes of providing better tools for policymakers to analyze and project trends and also to be better prepared to address the shifting sands of opioid use disorder in the United States.

They attempted to collect data on confirmed opioid overdose deaths from all 50 states and Washington, D.C. to assess what might have changed during the COVID-19 pandemic. Only nine states provided enough data for the analysis, which has been submitted to a peer reviewed publication.

These states were Alaska, Connecticut, Indiana, Massachusetts, North Carolina, Rhode Island, Colorado, Utah, and Wyoming.

“Drug overdose data are collected and reported more slowly than COVID-19 data,” Dr. Jalali said in a press release. The data reflected a lag time of about 4 to 8 months in Massachusetts and North Carolina to more than a year in Maryland and Ohio, he noted.

The reporting lag “has clouded the understanding of the effects of the COVID-19 pandemic on opioid-related overdose deaths,” said Dr. Jalali.

Commenting on the findings, Brandon Marshall, PhD, associate professor of epidemiology at Brown University, Providence, R.I, said that “the overall pattern of what’s being reported here is not surprising,” given the national trends seen in the CDC data.

“This paper adds a deeper dive into some of the sociodemographic trends that we’re starting to observe in specific states,” Dr. Marshall said.

Also commenting for this news organization, Brian Fuehrlein, MD, PhD, director of the psychiatric emergency department at the VA Connecticut Healthcare System in West Haven, Connecticut, noted that the current study “highlights things that we are currently seeing at VA Connecticut.”
 

Decrease in heroin, rise in fentanyl

The investigators found a significant reduction in overdose deaths that involved heroin in Alaska, Connecticut, Indiana, Massachusetts, North Carolina, and Rhode Island. That was a new trend for Alaska, Indiana, and Rhode Island, although with only 3 years of data, it’s hard to say whether it will continue, Dr. Jalali noted.

The decrease in heroin involvement seemed to continue a trend previously observed in Colorado, Connecticut, Massachusetts, and North Carolina.

In Connecticut, heroin was involved in 36% of deaths in 2018, 30% in 2019, and 16% in 2020, according to the study.

“We have begun seeing more and more heroin-negative, fentanyl-positive drug screens,” said Dr. Fuehrlein, who is also associate professor of psychiatry at Yale University, New Haven, Conn.

“There is a shift from fentanyl being an adulterant to fentanyl being what is sold and used exclusively,” he added.

In 2020, 92% (n = 887) of deaths in Connecticut involved synthetic opioids, continuing a trend. In Alaska, however, synthetic opioids were involved in 60% (44) of deaths, which is a big jump from 23% (9) in 2018.

Synthetic opioids were involved in the largest percentage of overdoses in all of the states studied. The fewest deaths, 17 (49%), occurred in Wyoming.

Cocaine is also increasingly found in addition to other substances in decedents. In Alaska, about 14% of individuals who overdosed in 2020 also had cocaine in their system, which was a jump from 2% in the prior year.

In Colorado, 19% (94) of those who died also had taken cocaine, up from 13% in 2019. Cocaine was also frequently found in those who died in the northeast: 39% (467) of those who died in Massachusetts, 29% (280) in Connecticut, and 47% (109) in Rhode Island.

There was also an increase in psychostimulants found in those who had died in Massachusetts in 2020.
 

More male overdoses in 2020

Results also showed that, compared to 2019, significantly more men died from overdoses in 2020 in Colorado (61% vs. 70%, P = .017) and Indiana (62% vs. 70%, P = .026).

This finding was unexpected, said Dr. Marshall, who has observed the same phenomenon in Rhode Island. He is the scientific director of PreventOverdoseRI, Rhode Island’s drug overdose surveillance and information dashboard.

Dr. Marshall and his colleagues conducted a study that also found disproportionate increases in overdoses among men. The findings of that study will be published in September.

“We’re still trying to wrap our head around why that is,” he said. He added that a deeper dive into the Rhode Island data showed that the deaths were increased especially among middle-aged men who had been diagnosed with depression and anxiety.

The same patterns were not seen among women in either Dr. Jalali’s study or his own analysis of the Rhode Island data, said Dr. Marshall.

“That suggests the COVID-19 pandemic impacted men who are at risk for overdose in some particularly severe way,” he noted.

Dr. Fuehrlein said he believes a variety of factors have led to an increase in overdose deaths during the pandemic, including the fact that many patients who would normally seek help avoided care or dropped out of treatment because of COVID fears. In addition, other support systems, such as group therapy and Narcotics Anonymous, were unavailable.

The pandemic increased stress, which can lead to worsening substance use, said Dr. Fuehrlein. He also noted that regular opioid suppliers were often not available, which led some to buy from different dealers, “which can lead to overdose if the fentanyl content is different.”
 

Identifying at-risk individuals

Dr. Jalali and colleagues note that clinicians and policymakers could use the new study to help identify and treat at-risk individuals.

“Practitioners and policy makers can use our findings to help them anticipate which groups of people might be most affected by opioid overdose and which types of policy interventions might be most effective given each state’s unique situation,” said lead study author Gian-Gabriel P. Garcia, PhD, in a press release. At the time of the study, Dr. Garcia was a postdoctoral fellow at Mass General and Harvard Medical School. He is currently an assistant professor at Georgia Tech, Atlanta.

Dr. Marshall pointed out that Dr. Jalali’s study is also relevant for emergency departments.

ED clinicians “are and will be seeing patients coming in who have no idea they were exposed to an opioid, nevermind fentanyl,” he said. ED clinicians can discuss with patients various harm reduction techniques, including the use of naloxone as well as test strips that can detect fentanyl in the drug supply, he added.

“Given the increasing use of fentanyl, which is very dangerous in overdose, clinicians need to be well versed in a harm reduction/overdose prevention approach to patient care,” Dr. Fuehrlein agreed.

A version of this article first appeared on Medscape.com.

Opioid overdose deaths were significantly higher during 2020, but occurrences were not homogeneous across nine states. Male deaths were higher than in the 2 previous years in two states, according to a new, granular examination of data collected by researchers at the Massachusetts General Hospital (Mass General), Boston.

The analysis also showed that synthetic opioids such as fentanyl played an outsized role in most of the states that were reviewed. Additional drugs of abuse found in decedents, such as cocaine and psychostimulants, were more prevalent in some states than in others.

The Centers for Disease Control and Prevention used provisional death data in its recent report. It found that opioid-related deaths substantially rose in 2020 and that synthetic opioids were a primary driver.

The current Mass General analysis provides a more timely and detailed dive, senior author Mohammad Jalali, PhD, who is a senior scientist at Mass General’s Institute for Technology Assessment, told this news organization.

The findings, which have not yet been peer reviewed, were published in MedRxiv.
 

Shifting sands of opioid use disorder

Dr. Jalali and colleagues used a decision analysis approach to study opioid data in the hopes of providing better tools for policymakers to analyze and project trends and also to be better prepared to address the shifting sands of opioid use disorder in the United States.

They attempted to collect data on confirmed opioid overdose deaths from all 50 states and Washington, D.C. to assess what might have changed during the COVID-19 pandemic. Only nine states provided enough data for the analysis, which has been submitted to a peer reviewed publication.

These states were Alaska, Connecticut, Indiana, Massachusetts, North Carolina, Rhode Island, Colorado, Utah, and Wyoming.

“Drug overdose data are collected and reported more slowly than COVID-19 data,” Dr. Jalali said in a press release. The data reflected a lag time of about 4 to 8 months in Massachusetts and North Carolina to more than a year in Maryland and Ohio, he noted.

The reporting lag “has clouded the understanding of the effects of the COVID-19 pandemic on opioid-related overdose deaths,” said Dr. Jalali.

Commenting on the findings, Brandon Marshall, PhD, associate professor of epidemiology at Brown University, Providence, R.I, said that “the overall pattern of what’s being reported here is not surprising,” given the national trends seen in the CDC data.

“This paper adds a deeper dive into some of the sociodemographic trends that we’re starting to observe in specific states,” Dr. Marshall said.

Also commenting for this news organization, Brian Fuehrlein, MD, PhD, director of the psychiatric emergency department at the VA Connecticut Healthcare System in West Haven, Connecticut, noted that the current study “highlights things that we are currently seeing at VA Connecticut.”
 

Decrease in heroin, rise in fentanyl

The investigators found a significant reduction in overdose deaths that involved heroin in Alaska, Connecticut, Indiana, Massachusetts, North Carolina, and Rhode Island. That was a new trend for Alaska, Indiana, and Rhode Island, although with only 3 years of data, it’s hard to say whether it will continue, Dr. Jalali noted.

The decrease in heroin involvement seemed to continue a trend previously observed in Colorado, Connecticut, Massachusetts, and North Carolina.

In Connecticut, heroin was involved in 36% of deaths in 2018, 30% in 2019, and 16% in 2020, according to the study.

“We have begun seeing more and more heroin-negative, fentanyl-positive drug screens,” said Dr. Fuehrlein, who is also associate professor of psychiatry at Yale University, New Haven, Conn.

“There is a shift from fentanyl being an adulterant to fentanyl being what is sold and used exclusively,” he added.

In 2020, 92% (n = 887) of deaths in Connecticut involved synthetic opioids, continuing a trend. In Alaska, however, synthetic opioids were involved in 60% (44) of deaths, which is a big jump from 23% (9) in 2018.

Synthetic opioids were involved in the largest percentage of overdoses in all of the states studied. The fewest deaths, 17 (49%), occurred in Wyoming.

Cocaine is also increasingly found in addition to other substances in decedents. In Alaska, about 14% of individuals who overdosed in 2020 also had cocaine in their system, which was a jump from 2% in the prior year.

In Colorado, 19% (94) of those who died also had taken cocaine, up from 13% in 2019. Cocaine was also frequently found in those who died in the northeast: 39% (467) of those who died in Massachusetts, 29% (280) in Connecticut, and 47% (109) in Rhode Island.

There was also an increase in psychostimulants found in those who had died in Massachusetts in 2020.
 

More male overdoses in 2020

Results also showed that, compared to 2019, significantly more men died from overdoses in 2020 in Colorado (61% vs. 70%, P = .017) and Indiana (62% vs. 70%, P = .026).

This finding was unexpected, said Dr. Marshall, who has observed the same phenomenon in Rhode Island. He is the scientific director of PreventOverdoseRI, Rhode Island’s drug overdose surveillance and information dashboard.

Dr. Marshall and his colleagues conducted a study that also found disproportionate increases in overdoses among men. The findings of that study will be published in September.

“We’re still trying to wrap our head around why that is,” he said. He added that a deeper dive into the Rhode Island data showed that the deaths were increased especially among middle-aged men who had been diagnosed with depression and anxiety.

The same patterns were not seen among women in either Dr. Jalali’s study or his own analysis of the Rhode Island data, said Dr. Marshall.

“That suggests the COVID-19 pandemic impacted men who are at risk for overdose in some particularly severe way,” he noted.

Dr. Fuehrlein said he believes a variety of factors have led to an increase in overdose deaths during the pandemic, including the fact that many patients who would normally seek help avoided care or dropped out of treatment because of COVID fears. In addition, other support systems, such as group therapy and Narcotics Anonymous, were unavailable.

The pandemic increased stress, which can lead to worsening substance use, said Dr. Fuehrlein. He also noted that regular opioid suppliers were often not available, which led some to buy from different dealers, “which can lead to overdose if the fentanyl content is different.”
 

Identifying at-risk individuals

Dr. Jalali and colleagues note that clinicians and policymakers could use the new study to help identify and treat at-risk individuals.

“Practitioners and policy makers can use our findings to help them anticipate which groups of people might be most affected by opioid overdose and which types of policy interventions might be most effective given each state’s unique situation,” said lead study author Gian-Gabriel P. Garcia, PhD, in a press release. At the time of the study, Dr. Garcia was a postdoctoral fellow at Mass General and Harvard Medical School. He is currently an assistant professor at Georgia Tech, Atlanta.

Dr. Marshall pointed out that Dr. Jalali’s study is also relevant for emergency departments.

ED clinicians “are and will be seeing patients coming in who have no idea they were exposed to an opioid, nevermind fentanyl,” he said. ED clinicians can discuss with patients various harm reduction techniques, including the use of naloxone as well as test strips that can detect fentanyl in the drug supply, he added.

“Given the increasing use of fentanyl, which is very dangerous in overdose, clinicians need to be well versed in a harm reduction/overdose prevention approach to patient care,” Dr. Fuehrlein agreed.

A version of this article first appeared on Medscape.com.

Opioid overdose deaths were significantly higher during 2020, but occurrences were not homogeneous across nine states. Male deaths were higher than in the 2 previous years in two states, according to a new, granular examination of data collected by researchers at the Massachusetts General Hospital (Mass General), Boston.

The analysis also showed that synthetic opioids such as fentanyl played an outsized role in most of the states that were reviewed. Additional drugs of abuse found in decedents, such as cocaine and psychostimulants, were more prevalent in some states than in others.

The Centers for Disease Control and Prevention used provisional death data in its recent report. It found that opioid-related deaths substantially rose in 2020 and that synthetic opioids were a primary driver.

The current Mass General analysis provides a more timely and detailed dive, senior author Mohammad Jalali, PhD, who is a senior scientist at Mass General’s Institute for Technology Assessment, told this news organization.

The findings, which have not yet been peer reviewed, were published in MedRxiv.
 

Shifting sands of opioid use disorder

Dr. Jalali and colleagues used a decision analysis approach to study opioid data in the hopes of providing better tools for policymakers to analyze and project trends and also to be better prepared to address the shifting sands of opioid use disorder in the United States.

They attempted to collect data on confirmed opioid overdose deaths from all 50 states and Washington, D.C. to assess what might have changed during the COVID-19 pandemic. Only nine states provided enough data for the analysis, which has been submitted to a peer reviewed publication.

These states were Alaska, Connecticut, Indiana, Massachusetts, North Carolina, Rhode Island, Colorado, Utah, and Wyoming.

“Drug overdose data are collected and reported more slowly than COVID-19 data,” Dr. Jalali said in a press release. The data reflected a lag time of about 4 to 8 months in Massachusetts and North Carolina to more than a year in Maryland and Ohio, he noted.

The reporting lag “has clouded the understanding of the effects of the COVID-19 pandemic on opioid-related overdose deaths,” said Dr. Jalali.

Commenting on the findings, Brandon Marshall, PhD, associate professor of epidemiology at Brown University, Providence, R.I, said that “the overall pattern of what’s being reported here is not surprising,” given the national trends seen in the CDC data.

“This paper adds a deeper dive into some of the sociodemographic trends that we’re starting to observe in specific states,” Dr. Marshall said.

Also commenting for this news organization, Brian Fuehrlein, MD, PhD, director of the psychiatric emergency department at the VA Connecticut Healthcare System in West Haven, Connecticut, noted that the current study “highlights things that we are currently seeing at VA Connecticut.”
 

Decrease in heroin, rise in fentanyl

The investigators found a significant reduction in overdose deaths that involved heroin in Alaska, Connecticut, Indiana, Massachusetts, North Carolina, and Rhode Island. That was a new trend for Alaska, Indiana, and Rhode Island, although with only 3 years of data, it’s hard to say whether it will continue, Dr. Jalali noted.

The decrease in heroin involvement seemed to continue a trend previously observed in Colorado, Connecticut, Massachusetts, and North Carolina.

In Connecticut, heroin was involved in 36% of deaths in 2018, 30% in 2019, and 16% in 2020, according to the study.

“We have begun seeing more and more heroin-negative, fentanyl-positive drug screens,” said Dr. Fuehrlein, who is also associate professor of psychiatry at Yale University, New Haven, Conn.

“There is a shift from fentanyl being an adulterant to fentanyl being what is sold and used exclusively,” he added.

In 2020, 92% (n = 887) of deaths in Connecticut involved synthetic opioids, continuing a trend. In Alaska, however, synthetic opioids were involved in 60% (44) of deaths, which is a big jump from 23% (9) in 2018.

Synthetic opioids were involved in the largest percentage of overdoses in all of the states studied. The fewest deaths, 17 (49%), occurred in Wyoming.

Cocaine is also increasingly found in addition to other substances in decedents. In Alaska, about 14% of individuals who overdosed in 2020 also had cocaine in their system, which was a jump from 2% in the prior year.

In Colorado, 19% (94) of those who died also had taken cocaine, up from 13% in 2019. Cocaine was also frequently found in those who died in the northeast: 39% (467) of those who died in Massachusetts, 29% (280) in Connecticut, and 47% (109) in Rhode Island.

There was also an increase in psychostimulants found in those who had died in Massachusetts in 2020.
 

More male overdoses in 2020

Results also showed that, compared to 2019, significantly more men died from overdoses in 2020 in Colorado (61% vs. 70%, P = .017) and Indiana (62% vs. 70%, P = .026).

This finding was unexpected, said Dr. Marshall, who has observed the same phenomenon in Rhode Island. He is the scientific director of PreventOverdoseRI, Rhode Island’s drug overdose surveillance and information dashboard.

Dr. Marshall and his colleagues conducted a study that also found disproportionate increases in overdoses among men. The findings of that study will be published in September.

“We’re still trying to wrap our head around why that is,” he said. He added that a deeper dive into the Rhode Island data showed that the deaths were increased especially among middle-aged men who had been diagnosed with depression and anxiety.

The same patterns were not seen among women in either Dr. Jalali’s study or his own analysis of the Rhode Island data, said Dr. Marshall.

“That suggests the COVID-19 pandemic impacted men who are at risk for overdose in some particularly severe way,” he noted.

Dr. Fuehrlein said he believes a variety of factors have led to an increase in overdose deaths during the pandemic, including the fact that many patients who would normally seek help avoided care or dropped out of treatment because of COVID fears. In addition, other support systems, such as group therapy and Narcotics Anonymous, were unavailable.

The pandemic increased stress, which can lead to worsening substance use, said Dr. Fuehrlein. He also noted that regular opioid suppliers were often not available, which led some to buy from different dealers, “which can lead to overdose if the fentanyl content is different.”
 

Identifying at-risk individuals

Dr. Jalali and colleagues note that clinicians and policymakers could use the new study to help identify and treat at-risk individuals.

“Practitioners and policy makers can use our findings to help them anticipate which groups of people might be most affected by opioid overdose and which types of policy interventions might be most effective given each state’s unique situation,” said lead study author Gian-Gabriel P. Garcia, PhD, in a press release. At the time of the study, Dr. Garcia was a postdoctoral fellow at Mass General and Harvard Medical School. He is currently an assistant professor at Georgia Tech, Atlanta.

Dr. Marshall pointed out that Dr. Jalali’s study is also relevant for emergency departments.

ED clinicians “are and will be seeing patients coming in who have no idea they were exposed to an opioid, nevermind fentanyl,” he said. ED clinicians can discuss with patients various harm reduction techniques, including the use of naloxone as well as test strips that can detect fentanyl in the drug supply, he added.

“Given the increasing use of fentanyl, which is very dangerous in overdose, clinicians need to be well versed in a harm reduction/overdose prevention approach to patient care,” Dr. Fuehrlein agreed.

A version of this article first appeared on Medscape.com.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.

Emerging evidence suggests that autoimmunity plays a role in postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and that targeting autoantibodies could be a promising treatment approach.

The same may also apply to many cases of “long COVID,” in which many of the symptoms overlap with those of ME/CFS, Carmen Scheibenbogen, MD, professor of clinical immunology and director of the Institute for Medical Immunology, Charité University Medicine, Berlin, said during the annual meeting of the International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.

Several groups, including Dr. Scheibenbogen’s, have reported finding autoantibodies against neurotransmitter receptor antigens in people with ME/CFS. And, in a paper published in the Journal of Clinical Medicine the day that Dr. Scheibenbogen spoke at the meeting, her team reported significant correlations between autoantibodies to vasoregulative G-protein–coupled receptors and symptom severity, autonomic dysfunction, and disability among 116 patients with infection-triggered ME/CFS who were diagnosed using the symptom-based 2003 Canadian consensus criteria.

People with ME/CFS are also more likely to have genetic risk factors associated with autoimmunity and personal and/or family histories of autoimmune conditions. And, clinical trials have demonstrated early success with various immunomodulatory treatments in subsets of people with ME/CFS, including endoxan, rituximab, and immunoadsorption.

“We have evidence that ME/CFS is an autoantibody-mediated disease, and we have evidence that autoantibody targeting is effective in this disease. So far ... we have few and underfinanced clinical studies, but the good news is we have promising emerging treatment options,” Dr. Scheibenbogen said.

Asked to comment, ME/CFS expert Anthony L. Komaroff, MD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, said: “There is already strong evidence that there are autoantibodies in ME/CFS. Dr. Scheibenbogen’s work is the latest and employs the latest technology. ... I would bet that autoantibodies to neural targets are likely to cause some of the symptoms of ME/CFS and some of the symptoms of long COVID.”

However, he cautioned, “that has not been proven, and even if it were proven you would have to demonstrate that treatments based on that theory worked.”

Dr. Komaroff said he views autoimmunity as a likely component of the ME/CFS spectrum, but not the only one. “My current view of this illness is that there’s a final common pathway in the brain that leads to the symptoms of the illness. But that final common pathway can be triggered by a variety of different things, one of which could be autoantibodies while another could be infection or inflammation in the brain.”
 

Emerging evidence points to autoimmunity

Dr. Scheibenbogen summarized the work published in this area over the past few years by her group and others.

In a comparison of ME/CFS patients with 201 healthy controls, significant associations were seen with two specific autoimmunity-related risk alleles only in the ME/CFS patients who reported acute onset of disease with an infection but not in those with ME/CFS without infection-triggered onset or the controls. Both genes play roles in regulating B- and T-cell activation.

Another recent study found associations with ME/CFS and major histocompatibility complex class II molecules, a typical feature of autoimmune diseases, in a comparison between 426 adult Norwegian ME/CFS patients who were diagnosed with the Canadian consensus criteria and 4,511 healthy, ethnically matched controls.

In a 2020 paper, Dr. Scheibenbogen and pharmacologist Klaus Wirth presented a “unifying hypothesis” of ME/CFS pathophysiology based on the finding of elevations in autoantibodies against beta₂-adrenergic receptors and muscarinic acetylcholine receptors in some individuals with the condition. Since both of those receptors are important vasodilators, their functional disturbance would be expected to cause vasoconstriction and hypoxemia, which would explain many of the symptoms of ME/CFS. This mechanism would align with other findings of muscular and cerebral hypoperfusion that correlate with fatigue, particularly post exertion, as well as metabolic changes that are in line with the concepts of hypoxemia and ischemia.

Further evidence for vascular dysfunction in ME/CFS came from her group’s study finding evidence of peripheral endothelial dysfunction that was associated with symptom severity in 35 adult patients. “Vasoconstriction, hypovolemia, and release of vasoactive and algesic mediators is probably a key pathomechanism of the disease,” Dr. Scheibenbogen said.
 

Treatments: Will targeting autoantibodies work?

In the second part of her talk, Dr. Scheibenbogen summarized clinical trials of the following treatment approaches that involve targeting autoantibodies as a way to alleviate ME/CFS symptoms:

Rituximab: Work on infusions of the B-cell depleting agent has been conducted by Norwegian researchers beginning in 2011 with a small randomized trial and an open-label, phase 2 study in 2015, both showing clinical responses in ME/CFS. However, a subsequent phase 3, randomized clinical trial of 151 patients, again diagnosed using the Canadian criteria, was negative.

There are several possible explanations for this, Dr. Scheibenbogen noted. For one, the maintenance dose had to be reduced because of a lack of financial support. “This was probably critical. The lower dose was insufficient to adequately deplete B cells.” Also, there may have been a strong placebo response in the control group since they were being given better care than they normally would receive during the trial. “I think probably nobody will again do a rituximab trial. This was very disappointing for all of us. But, we still have other opportunities to follow this path,” she said.

Dr. Komaroff agreed. “I don’t think the failure of one drug that hits malignant B cells is proof against the autoimmune hypothesis per se. I think the evidence is that rituximab doesn’t work, but that doesn’t invalidate the autoimmunity hypothesis.”

Cyclophosphamide: The same Norwegian group also showed positive findings in an open-label, phase 2 trial of the immune-modifying drug cyclophosphamide in 22 of 40 patients. Interestingly, HLA risk alleles were much more common in responders than nonresponders, Dr. Scheibenbogen noted.

Immunoadsorption: This technique, similar to dialysis, involves separating out the blood plasma by centrifugation and removing IgG autoantibodies by a binding column, then returning the plasma back to the patient. It is used, primarily in Europe, to treat severe autoimmune diseases including dilative cardiomyopathy and refractory systemic lupus erythematosus (SLE).

Dr. Scheibenbogen’s group has conducted two studies of immunoadsorption in ME/CFS. In one, a 5-day procedure led to rapid symptom improvement in 7 of 10 patients, with sustained improvement in 3 patients after 2 years. Autoantibodies decreased rapidly in 9 of the 10 patients. In a follow-up study of five of the responders 2 years later, retreatment with a modified immunoadsorption protocol led to rapid and sustained improvement in four. Further study has been on hold because of the pandemic.

Next-gen IgG-targeting therapies: Another approach that could offer promise for ME/CFS involves therapies that block the Fc receptors of IgG. Several are in phase 1-3 trials for autoimmune conditions. One candidate drug, the Fc fragment efgartigimod, is currently in phase 3 trials for several conditions, including generalized myasthenia gravis, primary immune thrombocytopenia, and chronic inflammatory demyelinating polyneuropathy. Phase 3 trials are planned for the monoclonal antibody rozanolixizumab in those same conditions.

Newer-generation monoclonal antibodies targeting CD19 or CD20 that show benefit in various autoimmune conditions are another possibility for ME/CFS. These include ocrelizumab (Ocrevus), approved in the United States for treating relapsing and progressive multiple sclerosis and in trials for SLE; obinutuzumab (Gazyva), approved for treating lymphoma and also in development for SLE; and ublituximab, in phase 3 trials for multiple sclerosis.

“Most of them are more effective than rituximab,” Dr. Scheibenbogen noted, adding that “currently the data look quite promising. They are effective in different autoimmune diseases and they are quite well tolerated. There’s great hope now with COVID-19 that we can convince some companies to do such trials in ME/CFS as well.”

Dr. Scheibenbogen’s institution, the Charité Fatigue Center, has a patent for beta₂-adrenergic receptor antibodies for diagnosing ME/CFS under her name together with Celltrend. Dr. Komaroff has received personal fees from Serimmune.