Neurology

It remains difficult to distinguish anti-NMDA receptor encephalitis from a primary psychiatric disorder, but recent studies have identified clinical features and proposed screening criteria that could make it easier to identify these patients who would benefit from immunotherapy, according to an expert in the neurologic disease.

Epifantsev/Thinkstock

Most patients with confirmed anti-NMDA receptor encephalitis will experience substantial improvement after treatment with immunotherapy and other modalities, said Josep Dalmau, MD, PhD, professor at the Catalan Institute for Research and Advanced Studies at the University of Barcelona and adjunct professor of neurology at the University of Pennsylvania, Philadelphia.

“In our experience, being aggressive with immune therapy ... the patients do quite well, which means that basically 85%-90% of the patients substantially improved over the next few months,” Dr. Dalmau said at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

Identified for the first time a little more than a decade ago, anti-NMDA receptor encephalitis is a rare, immune-mediated disease that is usually found in children and young adults and is more common among women. It is frequently associated with ovarian tumors and teratomas, said Dr. Dalmau, and in about 90% of cases, patients will have prominent psychiatric and behavioral symptoms.

Patients develop IgG antibodies against the GluN1 subunit of the NMDA receptor. These autoantibodies represent not only a diagnostic marker of the disease, but are also pathogenic, altering NMDA receptor–related synaptic transmission, Dr. Dalmau said.

In several recent studies, investigators have attempted to cobble together a distinct phenotype on anti-NMDA receptor encephalitis to aid psychiatrists who might encounter patients with the disease, he said.

In one of the most recent studies, researchers combed the medical literature and found that, among 544 individuals with the disease, the most common psychiatric symptoms were agitation, seen in 59%, and psychotic symptoms (particularly visual-auditory hallucinations and disorganized behavior) in 54%; catatonia was seen in 42% of adults and 35% of children.

Several “red flags” could tip off clinicians to a diagnosis of anti-NMDA receptor encephalitis, according to a report from researchers in Berlin, Dr. Dalmau added. By picking up on those clinical signs, which included seizures, catatonia, autonomic instability, or hyperkinesia, the time from symptom onset to diagnosis could be cut in half, the researchers found.

There’s also a handy acronym that could serve as a mnemonic to pick up on “diagnostic clues” of anti-NMDA receptor encephalitis among patients with new-onset psychiatric symptoms, Dr. Dalmau said.

That acronym, published in a review article by Dr. Dalmau and colleagues, is SEARCH For NMDAR-A, covering, in order: sleep dysfunction, excitement, agitation, rapid onset, child and young adult predominance, history of psychiatric disease (absent), fluctuating catatonia, negative and positive symptoms, memory deficit, decreased verbal output, antipsychotic intolerance, rule out neuroleptic malignant syndrome, and of course, antibodies (though the final “A” also stands for additional testing, including magnetic resonance imaging, cerebrospinal fluid studies, and electroencephalogram).

While the disease can be lethal, Dr. Dalmau said most patients respond to immunotherapy, and if applicable, treatment of the underlying tumor can help. The most common first-line treatments include steroids, intravenous immunoglobulin, and plasma exchange, he said, while second-line treatments include the monoclonal anti-CD20 antibody rituximab and cyclophosphamide.

Beyond immunotherapy, patients may benefit from supportive care and psychiatric treatment. Benzodiazepines are well tolerated, but Dr. Dalmau said antipsychotic intolerance is frequent, and electroconvulsive therapy has “mixed results” in these patients.

The recovery process can take months and may be complicated by hypersomnia, hyperphagia, and hypersexuality, he added.

“Some patients improve dramatically in 1 month, but this is uncommon, really,” he said, adding that an early recovery may be a “red flag” that the underlying condition is something other than anti-NMDA receptor encephalitis.

Dr. Dalmau provided disclosures related to Cellex Foundation, Safra Foundation, Caixa Health Project Foundation, and Sage Therapeutics.

SOURCE: Dalmau J. APA 2020, Abstract.

It remains difficult to distinguish anti-NMDA receptor encephalitis from a primary psychiatric disorder, but recent studies have identified clinical features and proposed screening criteria that could make it easier to identify these patients who would benefit from immunotherapy, according to an expert in the neurologic disease.

Epifantsev/Thinkstock

Most patients with confirmed anti-NMDA receptor encephalitis will experience substantial improvement after treatment with immunotherapy and other modalities, said Josep Dalmau, MD, PhD, professor at the Catalan Institute for Research and Advanced Studies at the University of Barcelona and adjunct professor of neurology at the University of Pennsylvania, Philadelphia.

“In our experience, being aggressive with immune therapy ... the patients do quite well, which means that basically 85%-90% of the patients substantially improved over the next few months,” Dr. Dalmau said at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

Identified for the first time a little more than a decade ago, anti-NMDA receptor encephalitis is a rare, immune-mediated disease that is usually found in children and young adults and is more common among women. It is frequently associated with ovarian tumors and teratomas, said Dr. Dalmau, and in about 90% of cases, patients will have prominent psychiatric and behavioral symptoms.

Patients develop IgG antibodies against the GluN1 subunit of the NMDA receptor. These autoantibodies represent not only a diagnostic marker of the disease, but are also pathogenic, altering NMDA receptor–related synaptic transmission, Dr. Dalmau said.

In several recent studies, investigators have attempted to cobble together a distinct phenotype on anti-NMDA receptor encephalitis to aid psychiatrists who might encounter patients with the disease, he said.

In one of the most recent studies, researchers combed the medical literature and found that, among 544 individuals with the disease, the most common psychiatric symptoms were agitation, seen in 59%, and psychotic symptoms (particularly visual-auditory hallucinations and disorganized behavior) in 54%; catatonia was seen in 42% of adults and 35% of children.

Several “red flags” could tip off clinicians to a diagnosis of anti-NMDA receptor encephalitis, according to a report from researchers in Berlin, Dr. Dalmau added. By picking up on those clinical signs, which included seizures, catatonia, autonomic instability, or hyperkinesia, the time from symptom onset to diagnosis could be cut in half, the researchers found.

There’s also a handy acronym that could serve as a mnemonic to pick up on “diagnostic clues” of anti-NMDA receptor encephalitis among patients with new-onset psychiatric symptoms, Dr. Dalmau said.

That acronym, published in a review article by Dr. Dalmau and colleagues, is SEARCH For NMDAR-A, covering, in order: sleep dysfunction, excitement, agitation, rapid onset, child and young adult predominance, history of psychiatric disease (absent), fluctuating catatonia, negative and positive symptoms, memory deficit, decreased verbal output, antipsychotic intolerance, rule out neuroleptic malignant syndrome, and of course, antibodies (though the final “A” also stands for additional testing, including magnetic resonance imaging, cerebrospinal fluid studies, and electroencephalogram).

While the disease can be lethal, Dr. Dalmau said most patients respond to immunotherapy, and if applicable, treatment of the underlying tumor can help. The most common first-line treatments include steroids, intravenous immunoglobulin, and plasma exchange, he said, while second-line treatments include the monoclonal anti-CD20 antibody rituximab and cyclophosphamide.

Beyond immunotherapy, patients may benefit from supportive care and psychiatric treatment. Benzodiazepines are well tolerated, but Dr. Dalmau said antipsychotic intolerance is frequent, and electroconvulsive therapy has “mixed results” in these patients.

The recovery process can take months and may be complicated by hypersomnia, hyperphagia, and hypersexuality, he added.

“Some patients improve dramatically in 1 month, but this is uncommon, really,” he said, adding that an early recovery may be a “red flag” that the underlying condition is something other than anti-NMDA receptor encephalitis.

Dr. Dalmau provided disclosures related to Cellex Foundation, Safra Foundation, Caixa Health Project Foundation, and Sage Therapeutics.

SOURCE: Dalmau J. APA 2020, Abstract.

It remains difficult to distinguish anti-NMDA receptor encephalitis from a primary psychiatric disorder, but recent studies have identified clinical features and proposed screening criteria that could make it easier to identify these patients who would benefit from immunotherapy, according to an expert in the neurologic disease.

Epifantsev/Thinkstock

Most patients with confirmed anti-NMDA receptor encephalitis will experience substantial improvement after treatment with immunotherapy and other modalities, said Josep Dalmau, MD, PhD, professor at the Catalan Institute for Research and Advanced Studies at the University of Barcelona and adjunct professor of neurology at the University of Pennsylvania, Philadelphia.

“In our experience, being aggressive with immune therapy ... the patients do quite well, which means that basically 85%-90% of the patients substantially improved over the next few months,” Dr. Dalmau said at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

Identified for the first time a little more than a decade ago, anti-NMDA receptor encephalitis is a rare, immune-mediated disease that is usually found in children and young adults and is more common among women. It is frequently associated with ovarian tumors and teratomas, said Dr. Dalmau, and in about 90% of cases, patients will have prominent psychiatric and behavioral symptoms.

Patients develop IgG antibodies against the GluN1 subunit of the NMDA receptor. These autoantibodies represent not only a diagnostic marker of the disease, but are also pathogenic, altering NMDA receptor–related synaptic transmission, Dr. Dalmau said.

In several recent studies, investigators have attempted to cobble together a distinct phenotype on anti-NMDA receptor encephalitis to aid psychiatrists who might encounter patients with the disease, he said.

In one of the most recent studies, researchers combed the medical literature and found that, among 544 individuals with the disease, the most common psychiatric symptoms were agitation, seen in 59%, and psychotic symptoms (particularly visual-auditory hallucinations and disorganized behavior) in 54%; catatonia was seen in 42% of adults and 35% of children.

Several “red flags” could tip off clinicians to a diagnosis of anti-NMDA receptor encephalitis, according to a report from researchers in Berlin, Dr. Dalmau added. By picking up on those clinical signs, which included seizures, catatonia, autonomic instability, or hyperkinesia, the time from symptom onset to diagnosis could be cut in half, the researchers found.

There’s also a handy acronym that could serve as a mnemonic to pick up on “diagnostic clues” of anti-NMDA receptor encephalitis among patients with new-onset psychiatric symptoms, Dr. Dalmau said.

That acronym, published in a review article by Dr. Dalmau and colleagues, is SEARCH For NMDAR-A, covering, in order: sleep dysfunction, excitement, agitation, rapid onset, child and young adult predominance, history of psychiatric disease (absent), fluctuating catatonia, negative and positive symptoms, memory deficit, decreased verbal output, antipsychotic intolerance, rule out neuroleptic malignant syndrome, and of course, antibodies (though the final “A” also stands for additional testing, including magnetic resonance imaging, cerebrospinal fluid studies, and electroencephalogram).

While the disease can be lethal, Dr. Dalmau said most patients respond to immunotherapy, and if applicable, treatment of the underlying tumor can help. The most common first-line treatments include steroids, intravenous immunoglobulin, and plasma exchange, he said, while second-line treatments include the monoclonal anti-CD20 antibody rituximab and cyclophosphamide.

Beyond immunotherapy, patients may benefit from supportive care and psychiatric treatment. Benzodiazepines are well tolerated, but Dr. Dalmau said antipsychotic intolerance is frequent, and electroconvulsive therapy has “mixed results” in these patients.

The recovery process can take months and may be complicated by hypersomnia, hyperphagia, and hypersexuality, he added.

“Some patients improve dramatically in 1 month, but this is uncommon, really,” he said, adding that an early recovery may be a “red flag” that the underlying condition is something other than anti-NMDA receptor encephalitis.

Dr. Dalmau provided disclosures related to Cellex Foundation, Safra Foundation, Caixa Health Project Foundation, and Sage Therapeutics.

SOURCE: Dalmau J. APA 2020, Abstract.

With some pivotal trials on hold, the COVID-19 pandemic is slowing the pace of research in Alzheimer’s disease, stroke, and multiple sclerosis (MS).

However, researchers remain determined to forge ahead – with many redesigning their studies, at least in part to optimize the safety of their participants and research staff.

Keeping people engaged while protocols are on hold; expanding normal safety considerations; and re-enlisting statisticians to keep their findings as significant as possible are just some of study survival strategies underway.
 

Alzheimer’s disease research on hold

The pandemic is having a significant impact on Alzheimer’s disease research, and medical research in general, says Heather Snyder, PhD, vice president, Medical & Scientific Relations at the Alzheimer’s Association.

“Many clinical trials worldwide are pausing, changing, or halting the testing of the drug or the intervention,” she told Medscape Medical News. “How the teams have adapted depends on the study,” she added. “As you can imagine, things are changing on a daily basis.”

The US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) trial, for example, is on hold until at least May 31. The Alzheimer’s Association is helping to implement and fund the study along with Wake Forest University Medical Center.

“We’re not randomizing participants at this point in time and the intervention — which is based on a team meeting, and there is a social aspect to that — has been paused,” Dr. Snyder said.

Another pivotal study underway is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (the A4 Study). Investigators are evaluating if an anti-amyloid antibody, solanezumab (Eli Lilly), can slow memory loss among people with amyloid on imaging but no symptoms of cognitive decline at baseline.

“The A4 Study is definitely continuing. However, in an effort to minimize risk to participants, site staff and study integrity, we have implemented an optional study hiatus for both the double-blind and open-label extension phases,” lead investigator Reisa Anne Sperling, MD, told Medscape Medical News.

“We wanted to prioritize the safety of our participants as well as the ability of participants to remain in the study … despite disruptions from the COVID-19 pandemic,” said Dr. Sperling, who is professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.

The ultimate goal is for A4 participants to receive the full number of planned infusions and assessments, even if it takes longer, she added.

Many Alzheimer’s disease researchers outside the United States face similar challenges. “As you probably are well aware, Spain is now in a complete lockdown. This has affected research centers like ours, the Barcelona Brain Research Center, and the way we work,” José Luís Molinuevo Guix, MD, PhD, told Medscape Medical News.

All participants in observational studies like the ALFA+ study and initiatives, as well as those in trials including PENSA and AB1601, “are not allowed, by law, to come in, hence from a safety perspective we are on good grounds,” added Dr. Molinuevo Guix, who directs the Alzheimer’s disease and other cognitive disorders unit at the Hospital Clinic de Barcelona.

The investigators are creating protocols for communicating with participants during the pandemic and for restarting visits safely after the lockdown has ended.
 

Stroke studies amended or suspended

A similar situation is occurring in stroke trials. Stroke is “obviously an acute disease, as well as a disease that requires secondary prevention,” Mitchell Elkind, MD, president-elect of the American Heart Association, told Medscape Medical News.

“One could argue that patients with stroke are going to be in the hospital anyway – why not enroll them in a study? They’re not incurring any additional risk,” he said. “But the staff have to come in to see them, and we’re really trying to avoid exposure.”

One ongoing trial, the Atrial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA), stopped randomly assigning new participants to secondary prevention with apixaban or aspirin because of COVID-19. However, Dr. Elkind and colleagues plan to provide medication to the 440 people already in the trial.

“Wherever possible, the study coordinators are shipping the drug to people and doing follow-up visits by phone or video,” said Dr. Elkind, chief of the Division of Neurology Clinical Outcomes Research and Population Sciences at Columbia University in New York City.

Protecting patients, staff, and ultimately society is a “major driving force in stopping the randomizations,” he stressed.

ARCADIA is part of the StrokeNet prevention trials network, run by the NIH’s National Institute of Neurologic Disorders and Stroke (NINDS). Additional pivotal trials include the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and the Multi-arm Optimization of Stroke Thrombolysis (MOST) studies, he said.

Joseph Broderick, MD, director of the national NIH StrokeNet, agreed that safety comes first. “It was the decision of the StrokeNet leadership and the principal investigators of the trials that we needed to hold recruitment of new patients while we worked on adapting processes of enrollment to ensure the safety of both patients and researchers interacting with study patients,” he told Medscape Medical News.

Potential risks vary based on the study intervention and the need for in-person interactions. Trials that include stimulation devices or physical therapy, for example, might be most affected, added Dr. Broderick, professor and director of the UC Gardner Neuroscience Institute at the University of Cincinnati in Ohio.

Nevertheless, “there are potential ways … to move as much as possible toward telemedicine and digital interactions during this time.”
 

Multiple challenges in multiple sclerosis

At the national level, the COVID-19 pandemic has had an “unprecedented impact on almost all the clinical trials funded by NINDS,” said Clinton Wright, MD, director of the Division of Clinical Research at NINDS. “Investigators have had to adapt quickly.”

Supplementing existing grants with money to conduct research on COVID-19 and pursuing research opportunities from different institutes are “some of the creative approaches [that] have come from the NIH [National Institutes of Health] itself,” Dr. Wright said. “Other creative approaches have come from investigators trying to keep their studies and trials going during the pandemic.”

In clinical trials, “everything from electronic consent to in-home research drug delivery is being brought to bear.”

“A few ongoing trials have been able to modify their protocols to obtain consent and carry out evaluations remotely by telephone or videoconferencing,” Dr. Wright said. “This is especially critical for trials that involve medical management of specific risk factors or conditions, where suspension of the trial could itself have adverse consequences due to reduced engagement with research participants.”

For participants already in MS studies, “each upcoming visit is assessed for whether it’s critical or could be done virtually or just skipped. If a person needs a treatment that cannot be postponed or skipped, they come in,” Jeffrey Cohen, MD, director of the Experimental Therapeutics Program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, told Medscape Medical News.

New study enrollment is largely on hold and study visits for existing participants are limited, said Dr. Cohen, who is also president of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Some of the major ongoing trials in MS are “looking at very fundamental questions in the field,” Dr. Cohen said. The Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS) and Traditional Versus Early Aggressive Therapy for Multiple Sclerosis (TREAT-MS) trials, for example, evaluate whether treatment should be initiated with one of the less efficacious agents with escalation as needed, or whether treatment should begin with a high-efficacy agent.

Both trials are currently on hold because of the pandemic, as is the Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) study.

“There has been a lot of interest in hematopoietic stem cell transplants and where they fit into our overall treatment strategy, and this is intended to provide a more definitive answer,” Dr. Cohen said.
 

Making the most of down time

“The pandemic has been challenging” in terms of ongoing MS research, said Benjamin M. Segal, MD, chair of the Department of Neurology and director of the Neuroscience Research Institute at the Ohio State University Wexner Medical Center, Columbus.

“With regard to the lab, our animal model experiments have been placed on hold. We have stopped collecting samples from clinical subjects for biomarker studies.

“However, my research team has been taking advantage of the time that has been freed up from bench work by analyzing data sets that had been placed aside, delving more deeply into the literature, and writing new grant proposals and articles,” he added.

Two of Dr. Segal’s trainees are writing review articles on the immunopathogenesis of MS and its treatment. Another postdoctoral candidate is writing a grant proposal to investigate how coinfection with a coronavirus modulates CNS pathology and the clinical course of an animal model of MS.

“I am asking my trainees to plan out experiments further in advance than they ever have before, so they are as prepared as possible to resume their research agendas once we are up and running again,” Dr. Segal said.

Confronting current challenges while planning for a future less disrupted by the pandemic is a common theme that emerges.

“The duration of this [pandemic] will dictate how we analyze the data at the end [for the US POINTER study]. There is a large group of statisticians working on this,” Dr. Snyder said.

Dr. Sperling of Harvard Medical School also remains undeterred. “This is definitely a challenging time, as we must not allow the COVID-19 to interfere with our essential mission to find a successful treatment to prevent cognitive decline in AD. We do need, however, to be as flexible as possible to protect our participants and minimize the impact to our overall study integrity,” she said.
 

NIH guidance

Dr. Molinuevo Guix, of the Barcelona Brain Research Center, is also determined to continue his Alzheimer’s disease research. “I am aware that after the crisis, there will be less [risk] but still a COVID-19 infection risk, so apart from trying to generate part of our visits virtually, we want to make sure we have all necessary safety measures in place. We remain very active to preserve the work we have done to keep up the fight against Alzheimer’s and dementia,” he said.

Such forward thinking also applies to major stroke trials, said Dr. Broderick of the University of Cincinnati. “As soon as we shut down enrollment in stroke trials, we immediately began to make plans about how and when we can restart our stroke trials,” he explained. “One of our trials can do every step of the trial process remotely without direct in-person interactions and will be able to restart soon.”

An individualized approach is needed, Dr. Broderick added. “For trials involving necessary in-person and hands-on assessments, we will need to consider how best to use protective equipment and expanded testing that will likely match the ongoing clinical care and requirements at a given institution.

“Even if a trial officially reopens enrollment, the decision to enroll locally will need to follow local institutional environment and guidelines. Thus, restart of trial enrollment will not likely be uniform, similar to how trials often start in the first place,” Dr. Broderick said.

The NIH published uniform standards for researchers across its institutes to help guide them during the pandemic. Future contingency plans also are underway at the NINDS.

“As the pandemic wanes and in-person research activities restart, it will be important to have in place safety measures that prevent a resurgence of the virus, such as proper personal protective equipment for staff and research participants, said Dr. Wright, the clinical research director at NINDS.

For clinical trials, NINDS is prepared to provide supplemental funds to trial investigators to help support additional activities undertaken as a result of the pandemic.

“This has been an instructive experience. The pandemic will end, and we will resume much of our old patterns of behavior,” said Ohio State’s Dr. Segal. “But some of the strategies that we have employed to get through this time will continue to influence the way we communicate information, plan experiments, and prioritize research activities in the future, to good effect.”

Drs. Snyder, Sperling, Molinuevo Guix, Elkind, Broderick, Wright, Cohen, and Segal have disclosed no relevant disclosures.

This story first appeared on Medscape.com.

With some pivotal trials on hold, the COVID-19 pandemic is slowing the pace of research in Alzheimer’s disease, stroke, and multiple sclerosis (MS).

However, researchers remain determined to forge ahead – with many redesigning their studies, at least in part to optimize the safety of their participants and research staff.

Keeping people engaged while protocols are on hold; expanding normal safety considerations; and re-enlisting statisticians to keep their findings as significant as possible are just some of study survival strategies underway.
 

Alzheimer’s disease research on hold

The pandemic is having a significant impact on Alzheimer’s disease research, and medical research in general, says Heather Snyder, PhD, vice president, Medical & Scientific Relations at the Alzheimer’s Association.

“Many clinical trials worldwide are pausing, changing, or halting the testing of the drug or the intervention,” she told Medscape Medical News. “How the teams have adapted depends on the study,” she added. “As you can imagine, things are changing on a daily basis.”

The US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) trial, for example, is on hold until at least May 31. The Alzheimer’s Association is helping to implement and fund the study along with Wake Forest University Medical Center.

“We’re not randomizing participants at this point in time and the intervention — which is based on a team meeting, and there is a social aspect to that — has been paused,” Dr. Snyder said.

Another pivotal study underway is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (the A4 Study). Investigators are evaluating if an anti-amyloid antibody, solanezumab (Eli Lilly), can slow memory loss among people with amyloid on imaging but no symptoms of cognitive decline at baseline.

“The A4 Study is definitely continuing. However, in an effort to minimize risk to participants, site staff and study integrity, we have implemented an optional study hiatus for both the double-blind and open-label extension phases,” lead investigator Reisa Anne Sperling, MD, told Medscape Medical News.

“We wanted to prioritize the safety of our participants as well as the ability of participants to remain in the study … despite disruptions from the COVID-19 pandemic,” said Dr. Sperling, who is professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.

The ultimate goal is for A4 participants to receive the full number of planned infusions and assessments, even if it takes longer, she added.

Many Alzheimer’s disease researchers outside the United States face similar challenges. “As you probably are well aware, Spain is now in a complete lockdown. This has affected research centers like ours, the Barcelona Brain Research Center, and the way we work,” José Luís Molinuevo Guix, MD, PhD, told Medscape Medical News.

All participants in observational studies like the ALFA+ study and initiatives, as well as those in trials including PENSA and AB1601, “are not allowed, by law, to come in, hence from a safety perspective we are on good grounds,” added Dr. Molinuevo Guix, who directs the Alzheimer’s disease and other cognitive disorders unit at the Hospital Clinic de Barcelona.

The investigators are creating protocols for communicating with participants during the pandemic and for restarting visits safely after the lockdown has ended.
 

Stroke studies amended or suspended

A similar situation is occurring in stroke trials. Stroke is “obviously an acute disease, as well as a disease that requires secondary prevention,” Mitchell Elkind, MD, president-elect of the American Heart Association, told Medscape Medical News.

“One could argue that patients with stroke are going to be in the hospital anyway – why not enroll them in a study? They’re not incurring any additional risk,” he said. “But the staff have to come in to see them, and we’re really trying to avoid exposure.”

One ongoing trial, the Atrial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA), stopped randomly assigning new participants to secondary prevention with apixaban or aspirin because of COVID-19. However, Dr. Elkind and colleagues plan to provide medication to the 440 people already in the trial.

“Wherever possible, the study coordinators are shipping the drug to people and doing follow-up visits by phone or video,” said Dr. Elkind, chief of the Division of Neurology Clinical Outcomes Research and Population Sciences at Columbia University in New York City.

Protecting patients, staff, and ultimately society is a “major driving force in stopping the randomizations,” he stressed.

ARCADIA is part of the StrokeNet prevention trials network, run by the NIH’s National Institute of Neurologic Disorders and Stroke (NINDS). Additional pivotal trials include the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and the Multi-arm Optimization of Stroke Thrombolysis (MOST) studies, he said.

Joseph Broderick, MD, director of the national NIH StrokeNet, agreed that safety comes first. “It was the decision of the StrokeNet leadership and the principal investigators of the trials that we needed to hold recruitment of new patients while we worked on adapting processes of enrollment to ensure the safety of both patients and researchers interacting with study patients,” he told Medscape Medical News.

Potential risks vary based on the study intervention and the need for in-person interactions. Trials that include stimulation devices or physical therapy, for example, might be most affected, added Dr. Broderick, professor and director of the UC Gardner Neuroscience Institute at the University of Cincinnati in Ohio.

Nevertheless, “there are potential ways … to move as much as possible toward telemedicine and digital interactions during this time.”
 

Multiple challenges in multiple sclerosis

At the national level, the COVID-19 pandemic has had an “unprecedented impact on almost all the clinical trials funded by NINDS,” said Clinton Wright, MD, director of the Division of Clinical Research at NINDS. “Investigators have had to adapt quickly.”

Supplementing existing grants with money to conduct research on COVID-19 and pursuing research opportunities from different institutes are “some of the creative approaches [that] have come from the NIH [National Institutes of Health] itself,” Dr. Wright said. “Other creative approaches have come from investigators trying to keep their studies and trials going during the pandemic.”

In clinical trials, “everything from electronic consent to in-home research drug delivery is being brought to bear.”

“A few ongoing trials have been able to modify their protocols to obtain consent and carry out evaluations remotely by telephone or videoconferencing,” Dr. Wright said. “This is especially critical for trials that involve medical management of specific risk factors or conditions, where suspension of the trial could itself have adverse consequences due to reduced engagement with research participants.”

For participants already in MS studies, “each upcoming visit is assessed for whether it’s critical or could be done virtually or just skipped. If a person needs a treatment that cannot be postponed or skipped, they come in,” Jeffrey Cohen, MD, director of the Experimental Therapeutics Program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, told Medscape Medical News.

New study enrollment is largely on hold and study visits for existing participants are limited, said Dr. Cohen, who is also president of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Some of the major ongoing trials in MS are “looking at very fundamental questions in the field,” Dr. Cohen said. The Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS) and Traditional Versus Early Aggressive Therapy for Multiple Sclerosis (TREAT-MS) trials, for example, evaluate whether treatment should be initiated with one of the less efficacious agents with escalation as needed, or whether treatment should begin with a high-efficacy agent.

Both trials are currently on hold because of the pandemic, as is the Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) study.

“There has been a lot of interest in hematopoietic stem cell transplants and where they fit into our overall treatment strategy, and this is intended to provide a more definitive answer,” Dr. Cohen said.
 

Making the most of down time

“The pandemic has been challenging” in terms of ongoing MS research, said Benjamin M. Segal, MD, chair of the Department of Neurology and director of the Neuroscience Research Institute at the Ohio State University Wexner Medical Center, Columbus.

“With regard to the lab, our animal model experiments have been placed on hold. We have stopped collecting samples from clinical subjects for biomarker studies.

“However, my research team has been taking advantage of the time that has been freed up from bench work by analyzing data sets that had been placed aside, delving more deeply into the literature, and writing new grant proposals and articles,” he added.

Two of Dr. Segal’s trainees are writing review articles on the immunopathogenesis of MS and its treatment. Another postdoctoral candidate is writing a grant proposal to investigate how coinfection with a coronavirus modulates CNS pathology and the clinical course of an animal model of MS.

“I am asking my trainees to plan out experiments further in advance than they ever have before, so they are as prepared as possible to resume their research agendas once we are up and running again,” Dr. Segal said.

Confronting current challenges while planning for a future less disrupted by the pandemic is a common theme that emerges.

“The duration of this [pandemic] will dictate how we analyze the data at the end [for the US POINTER study]. There is a large group of statisticians working on this,” Dr. Snyder said.

Dr. Sperling of Harvard Medical School also remains undeterred. “This is definitely a challenging time, as we must not allow the COVID-19 to interfere with our essential mission to find a successful treatment to prevent cognitive decline in AD. We do need, however, to be as flexible as possible to protect our participants and minimize the impact to our overall study integrity,” she said.
 

NIH guidance

Dr. Molinuevo Guix, of the Barcelona Brain Research Center, is also determined to continue his Alzheimer’s disease research. “I am aware that after the crisis, there will be less [risk] but still a COVID-19 infection risk, so apart from trying to generate part of our visits virtually, we want to make sure we have all necessary safety measures in place. We remain very active to preserve the work we have done to keep up the fight against Alzheimer’s and dementia,” he said.

Such forward thinking also applies to major stroke trials, said Dr. Broderick of the University of Cincinnati. “As soon as we shut down enrollment in stroke trials, we immediately began to make plans about how and when we can restart our stroke trials,” he explained. “One of our trials can do every step of the trial process remotely without direct in-person interactions and will be able to restart soon.”

An individualized approach is needed, Dr. Broderick added. “For trials involving necessary in-person and hands-on assessments, we will need to consider how best to use protective equipment and expanded testing that will likely match the ongoing clinical care and requirements at a given institution.

“Even if a trial officially reopens enrollment, the decision to enroll locally will need to follow local institutional environment and guidelines. Thus, restart of trial enrollment will not likely be uniform, similar to how trials often start in the first place,” Dr. Broderick said.

The NIH published uniform standards for researchers across its institutes to help guide them during the pandemic. Future contingency plans also are underway at the NINDS.

“As the pandemic wanes and in-person research activities restart, it will be important to have in place safety measures that prevent a resurgence of the virus, such as proper personal protective equipment for staff and research participants, said Dr. Wright, the clinical research director at NINDS.

For clinical trials, NINDS is prepared to provide supplemental funds to trial investigators to help support additional activities undertaken as a result of the pandemic.

“This has been an instructive experience. The pandemic will end, and we will resume much of our old patterns of behavior,” said Ohio State’s Dr. Segal. “But some of the strategies that we have employed to get through this time will continue to influence the way we communicate information, plan experiments, and prioritize research activities in the future, to good effect.”

Drs. Snyder, Sperling, Molinuevo Guix, Elkind, Broderick, Wright, Cohen, and Segal have disclosed no relevant disclosures.

This story first appeared on Medscape.com.

With some pivotal trials on hold, the COVID-19 pandemic is slowing the pace of research in Alzheimer’s disease, stroke, and multiple sclerosis (MS).

However, researchers remain determined to forge ahead – with many redesigning their studies, at least in part to optimize the safety of their participants and research staff.

Keeping people engaged while protocols are on hold; expanding normal safety considerations; and re-enlisting statisticians to keep their findings as significant as possible are just some of study survival strategies underway.
 

Alzheimer’s disease research on hold

The pandemic is having a significant impact on Alzheimer’s disease research, and medical research in general, says Heather Snyder, PhD, vice president, Medical & Scientific Relations at the Alzheimer’s Association.

“Many clinical trials worldwide are pausing, changing, or halting the testing of the drug or the intervention,” she told Medscape Medical News. “How the teams have adapted depends on the study,” she added. “As you can imagine, things are changing on a daily basis.”

The US Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) trial, for example, is on hold until at least May 31. The Alzheimer’s Association is helping to implement and fund the study along with Wake Forest University Medical Center.

“We’re not randomizing participants at this point in time and the intervention — which is based on a team meeting, and there is a social aspect to that — has been paused,” Dr. Snyder said.

Another pivotal study underway is the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (the A4 Study). Investigators are evaluating if an anti-amyloid antibody, solanezumab (Eli Lilly), can slow memory loss among people with amyloid on imaging but no symptoms of cognitive decline at baseline.

“The A4 Study is definitely continuing. However, in an effort to minimize risk to participants, site staff and study integrity, we have implemented an optional study hiatus for both the double-blind and open-label extension phases,” lead investigator Reisa Anne Sperling, MD, told Medscape Medical News.

“We wanted to prioritize the safety of our participants as well as the ability of participants to remain in the study … despite disruptions from the COVID-19 pandemic,” said Dr. Sperling, who is professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital and Massachusetts General Hospital in Boston.

The ultimate goal is for A4 participants to receive the full number of planned infusions and assessments, even if it takes longer, she added.

Many Alzheimer’s disease researchers outside the United States face similar challenges. “As you probably are well aware, Spain is now in a complete lockdown. This has affected research centers like ours, the Barcelona Brain Research Center, and the way we work,” José Luís Molinuevo Guix, MD, PhD, told Medscape Medical News.

All participants in observational studies like the ALFA+ study and initiatives, as well as those in trials including PENSA and AB1601, “are not allowed, by law, to come in, hence from a safety perspective we are on good grounds,” added Dr. Molinuevo Guix, who directs the Alzheimer’s disease and other cognitive disorders unit at the Hospital Clinic de Barcelona.

The investigators are creating protocols for communicating with participants during the pandemic and for restarting visits safely after the lockdown has ended.
 

Stroke studies amended or suspended

A similar situation is occurring in stroke trials. Stroke is “obviously an acute disease, as well as a disease that requires secondary prevention,” Mitchell Elkind, MD, president-elect of the American Heart Association, told Medscape Medical News.

“One could argue that patients with stroke are going to be in the hospital anyway – why not enroll them in a study? They’re not incurring any additional risk,” he said. “But the staff have to come in to see them, and we’re really trying to avoid exposure.”

One ongoing trial, the Atrial Cardiopathy and Antithrombotic Drugs In Prevention After Cryptogenic Stroke (ARCADIA), stopped randomly assigning new participants to secondary prevention with apixaban or aspirin because of COVID-19. However, Dr. Elkind and colleagues plan to provide medication to the 440 people already in the trial.

“Wherever possible, the study coordinators are shipping the drug to people and doing follow-up visits by phone or video,” said Dr. Elkind, chief of the Division of Neurology Clinical Outcomes Research and Population Sciences at Columbia University in New York City.

Protecting patients, staff, and ultimately society is a “major driving force in stopping the randomizations,” he stressed.

ARCADIA is part of the StrokeNet prevention trials network, run by the NIH’s National Institute of Neurologic Disorders and Stroke (NINDS). Additional pivotal trials include the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and the Multi-arm Optimization of Stroke Thrombolysis (MOST) studies, he said.

Joseph Broderick, MD, director of the national NIH StrokeNet, agreed that safety comes first. “It was the decision of the StrokeNet leadership and the principal investigators of the trials that we needed to hold recruitment of new patients while we worked on adapting processes of enrollment to ensure the safety of both patients and researchers interacting with study patients,” he told Medscape Medical News.

Potential risks vary based on the study intervention and the need for in-person interactions. Trials that include stimulation devices or physical therapy, for example, might be most affected, added Dr. Broderick, professor and director of the UC Gardner Neuroscience Institute at the University of Cincinnati in Ohio.

Nevertheless, “there are potential ways … to move as much as possible toward telemedicine and digital interactions during this time.”
 

Multiple challenges in multiple sclerosis

At the national level, the COVID-19 pandemic has had an “unprecedented impact on almost all the clinical trials funded by NINDS,” said Clinton Wright, MD, director of the Division of Clinical Research at NINDS. “Investigators have had to adapt quickly.”

Supplementing existing grants with money to conduct research on COVID-19 and pursuing research opportunities from different institutes are “some of the creative approaches [that] have come from the NIH [National Institutes of Health] itself,” Dr. Wright said. “Other creative approaches have come from investigators trying to keep their studies and trials going during the pandemic.”

In clinical trials, “everything from electronic consent to in-home research drug delivery is being brought to bear.”

“A few ongoing trials have been able to modify their protocols to obtain consent and carry out evaluations remotely by telephone or videoconferencing,” Dr. Wright said. “This is especially critical for trials that involve medical management of specific risk factors or conditions, where suspension of the trial could itself have adverse consequences due to reduced engagement with research participants.”

For participants already in MS studies, “each upcoming visit is assessed for whether it’s critical or could be done virtually or just skipped. If a person needs a treatment that cannot be postponed or skipped, they come in,” Jeffrey Cohen, MD, director of the Experimental Therapeutics Program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, Ohio, told Medscape Medical News.

New study enrollment is largely on hold and study visits for existing participants are limited, said Dr. Cohen, who is also president of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Some of the major ongoing trials in MS are “looking at very fundamental questions in the field,” Dr. Cohen said. The Determining the Effectiveness of earLy Intensive Versus Escalation Approaches for RRMS (DELIVER-MS) and Traditional Versus Early Aggressive Therapy for Multiple Sclerosis (TREAT-MS) trials, for example, evaluate whether treatment should be initiated with one of the less efficacious agents with escalation as needed, or whether treatment should begin with a high-efficacy agent.

Both trials are currently on hold because of the pandemic, as is the Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) study.

“There has been a lot of interest in hematopoietic stem cell transplants and where they fit into our overall treatment strategy, and this is intended to provide a more definitive answer,” Dr. Cohen said.
 

Making the most of down time

“The pandemic has been challenging” in terms of ongoing MS research, said Benjamin M. Segal, MD, chair of the Department of Neurology and director of the Neuroscience Research Institute at the Ohio State University Wexner Medical Center, Columbus.

“With regard to the lab, our animal model experiments have been placed on hold. We have stopped collecting samples from clinical subjects for biomarker studies.

“However, my research team has been taking advantage of the time that has been freed up from bench work by analyzing data sets that had been placed aside, delving more deeply into the literature, and writing new grant proposals and articles,” he added.

Two of Dr. Segal’s trainees are writing review articles on the immunopathogenesis of MS and its treatment. Another postdoctoral candidate is writing a grant proposal to investigate how coinfection with a coronavirus modulates CNS pathology and the clinical course of an animal model of MS.

“I am asking my trainees to plan out experiments further in advance than they ever have before, so they are as prepared as possible to resume their research agendas once we are up and running again,” Dr. Segal said.

Confronting current challenges while planning for a future less disrupted by the pandemic is a common theme that emerges.

“The duration of this [pandemic] will dictate how we analyze the data at the end [for the US POINTER study]. There is a large group of statisticians working on this,” Dr. Snyder said.

Dr. Sperling of Harvard Medical School also remains undeterred. “This is definitely a challenging time, as we must not allow the COVID-19 to interfere with our essential mission to find a successful treatment to prevent cognitive decline in AD. We do need, however, to be as flexible as possible to protect our participants and minimize the impact to our overall study integrity,” she said.
 

NIH guidance

Dr. Molinuevo Guix, of the Barcelona Brain Research Center, is also determined to continue his Alzheimer’s disease research. “I am aware that after the crisis, there will be less [risk] but still a COVID-19 infection risk, so apart from trying to generate part of our visits virtually, we want to make sure we have all necessary safety measures in place. We remain very active to preserve the work we have done to keep up the fight against Alzheimer’s and dementia,” he said.

Such forward thinking also applies to major stroke trials, said Dr. Broderick of the University of Cincinnati. “As soon as we shut down enrollment in stroke trials, we immediately began to make plans about how and when we can restart our stroke trials,” he explained. “One of our trials can do every step of the trial process remotely without direct in-person interactions and will be able to restart soon.”

An individualized approach is needed, Dr. Broderick added. “For trials involving necessary in-person and hands-on assessments, we will need to consider how best to use protective equipment and expanded testing that will likely match the ongoing clinical care and requirements at a given institution.

“Even if a trial officially reopens enrollment, the decision to enroll locally will need to follow local institutional environment and guidelines. Thus, restart of trial enrollment will not likely be uniform, similar to how trials often start in the first place,” Dr. Broderick said.

The NIH published uniform standards for researchers across its institutes to help guide them during the pandemic. Future contingency plans also are underway at the NINDS.

“As the pandemic wanes and in-person research activities restart, it will be important to have in place safety measures that prevent a resurgence of the virus, such as proper personal protective equipment for staff and research participants, said Dr. Wright, the clinical research director at NINDS.

For clinical trials, NINDS is prepared to provide supplemental funds to trial investigators to help support additional activities undertaken as a result of the pandemic.

“This has been an instructive experience. The pandemic will end, and we will resume much of our old patterns of behavior,” said Ohio State’s Dr. Segal. “But some of the strategies that we have employed to get through this time will continue to influence the way we communicate information, plan experiments, and prioritize research activities in the future, to good effect.”

Drs. Snyder, Sperling, Molinuevo Guix, Elkind, Broderick, Wright, Cohen, and Segal have disclosed no relevant disclosures.

This story first appeared on Medscape.com.

Background: The use of multimodal non-opioid analgesics is a common practice to minimize postoperative pain and opioid analgesic use. There is limited high-quality evidence to confirm the synergistic effect and safety of acetaminophen and ibuprofen in the peripostoperative setting. The Paracetamol and NSAID in combination (PANSAID) trial investigated the analgesic efficacy and safety of four multimodal analgesic regimens after total hip arthroplasty.

The median morphine consumption in the 24 hours after surgery was significantly lower with ­full-strength acetaminophen-ibuprofen compared with acetaminophen monotherapy (20 mg vs. 36 mg, 99.6% confidence interval, 6.5-24; P < .001), which exceeded the prespecified 10-mg threshold for a minimal clinically important difference (MCID). The difference between acetaminophen-ibuprofen and ibuprofen monotherapy (20 mg vs. 26 mg) did not exceed the MCID, and was not clinically meaningful. The ­differences in morphine consumption with full-strength acetaminophen-ibuprofen compared to half-strength acetaminophen-ibuprofen (28 mg) and ibuprofen compared to acetaminophen monotherapy were not statistically significant.

Serious adverse events, the other primary outcome, within 90 days after surgery (15% in the ibuprofen group and 11% in the acetaminophen group, relative risk, 1.44; 97.5% CI, 0.79-2.64; P = .18) did not differ between acetaminophen monotherapy and ibuprofen monotherapy. Secondary outcomes included statistically significant analgesia (lower pain scores) at rest and with mobilization at 24 hours in the acetaminophen-ibuprofen group compared to the other groups.

An interesting observation was that acetaminophen-ibuprofen did not exceed the MCID compared to ibuprofen, which suggests that ibuprofen monotherapy may be a reasonable option for early postoperative analgesia.

Bottom line: Acetaminophen-ibuprofen reduced postoperative morphine use and had improved analgesia 24 hours after total hip arthroplasty, and was not associated with an increased 3-month risk of serious adverse events.

Citation: Thybo KH et al. Effect of combination of paracetamol (acetaminophen) and ibuprofen vs. either alone on patient-controlled morphine consumption in the first 24 hours after total hip arthroplasty. The PANSAID randomized clinical trial. JAMA. 2019;321(6):562-71.

Dr. Lambert is a hospital medicine clinician and addiction medicine specialist in the division of hospital medicine at Massachusetts General Hospital.

Background: The use of multimodal non-opioid analgesics is a common practice to minimize postoperative pain and opioid analgesic use. There is limited high-quality evidence to confirm the synergistic effect and safety of acetaminophen and ibuprofen in the peripostoperative setting. The Paracetamol and NSAID in combination (PANSAID) trial investigated the analgesic efficacy and safety of four multimodal analgesic regimens after total hip arthroplasty.

The median morphine consumption in the 24 hours after surgery was significantly lower with ­full-strength acetaminophen-ibuprofen compared with acetaminophen monotherapy (20 mg vs. 36 mg, 99.6% confidence interval, 6.5-24; P < .001), which exceeded the prespecified 10-mg threshold for a minimal clinically important difference (MCID). The difference between acetaminophen-ibuprofen and ibuprofen monotherapy (20 mg vs. 26 mg) did not exceed the MCID, and was not clinically meaningful. The ­differences in morphine consumption with full-strength acetaminophen-ibuprofen compared to half-strength acetaminophen-ibuprofen (28 mg) and ibuprofen compared to acetaminophen monotherapy were not statistically significant.

Serious adverse events, the other primary outcome, within 90 days after surgery (15% in the ibuprofen group and 11% in the acetaminophen group, relative risk, 1.44; 97.5% CI, 0.79-2.64; P = .18) did not differ between acetaminophen monotherapy and ibuprofen monotherapy. Secondary outcomes included statistically significant analgesia (lower pain scores) at rest and with mobilization at 24 hours in the acetaminophen-ibuprofen group compared to the other groups.

An interesting observation was that acetaminophen-ibuprofen did not exceed the MCID compared to ibuprofen, which suggests that ibuprofen monotherapy may be a reasonable option for early postoperative analgesia.

Bottom line: Acetaminophen-ibuprofen reduced postoperative morphine use and had improved analgesia 24 hours after total hip arthroplasty, and was not associated with an increased 3-month risk of serious adverse events.

Citation: Thybo KH et al. Effect of combination of paracetamol (acetaminophen) and ibuprofen vs. either alone on patient-controlled morphine consumption in the first 24 hours after total hip arthroplasty. The PANSAID randomized clinical trial. JAMA. 2019;321(6):562-71.

Dr. Lambert is a hospital medicine clinician and addiction medicine specialist in the division of hospital medicine at Massachusetts General Hospital.

Background: The use of multimodal non-opioid analgesics is a common practice to minimize postoperative pain and opioid analgesic use. There is limited high-quality evidence to confirm the synergistic effect and safety of acetaminophen and ibuprofen in the peripostoperative setting. The Paracetamol and NSAID in combination (PANSAID) trial investigated the analgesic efficacy and safety of four multimodal analgesic regimens after total hip arthroplasty.

The median morphine consumption in the 24 hours after surgery was significantly lower with ­full-strength acetaminophen-ibuprofen compared with acetaminophen monotherapy (20 mg vs. 36 mg, 99.6% confidence interval, 6.5-24; P < .001), which exceeded the prespecified 10-mg threshold for a minimal clinically important difference (MCID). The difference between acetaminophen-ibuprofen and ibuprofen monotherapy (20 mg vs. 26 mg) did not exceed the MCID, and was not clinically meaningful. The ­differences in morphine consumption with full-strength acetaminophen-ibuprofen compared to half-strength acetaminophen-ibuprofen (28 mg) and ibuprofen compared to acetaminophen monotherapy were not statistically significant.

Serious adverse events, the other primary outcome, within 90 days after surgery (15% in the ibuprofen group and 11% in the acetaminophen group, relative risk, 1.44; 97.5% CI, 0.79-2.64; P = .18) did not differ between acetaminophen monotherapy and ibuprofen monotherapy. Secondary outcomes included statistically significant analgesia (lower pain scores) at rest and with mobilization at 24 hours in the acetaminophen-ibuprofen group compared to the other groups.

An interesting observation was that acetaminophen-ibuprofen did not exceed the MCID compared to ibuprofen, which suggests that ibuprofen monotherapy may be a reasonable option for early postoperative analgesia.

Bottom line: Acetaminophen-ibuprofen reduced postoperative morphine use and had improved analgesia 24 hours after total hip arthroplasty, and was not associated with an increased 3-month risk of serious adverse events.

Citation: Thybo KH et al. Effect of combination of paracetamol (acetaminophen) and ibuprofen vs. either alone on patient-controlled morphine consumption in the first 24 hours after total hip arthroplasty. The PANSAID randomized clinical trial. JAMA. 2019;321(6):562-71.

Dr. Lambert is a hospital medicine clinician and addiction medicine specialist in the division of hospital medicine at Massachusetts General Hospital.

Background: Federal health system programs, including TRICARE for military personnel, spent $259 million in 2013 and $746 million in 2014 for compounded analgesic medications despite a dearth of efficacy data. The purpose of this trial was to evaluate the efficacy and functional impact of this class of medications for chronic localized pain.

The primary outcome was the average pain score at 1 month follow-up, based on self-recorded arithmetic mean pain scores in the preceding week. Secondary outcomes included mean worst pain over the past week, functional improvement (assessed by validated Short-Form 36 Health Survey scores), and satisfaction (measured on a 1 to 5 Likert scale) with the individual treatment regimen.

Patients had small improvements in average pain scores at 1 month in the compounded formulation and placebo subgroups in all pain type categories. No significant differences were noted in the average pain scores compared to baseline, functional improvement or satisfaction in the compounded formulation and placebo groups of the total cohort or in any of the subgroups.

Bottom line: Compounded topical analgesics are costly and ineffective in the treatment of all types of chronic localized pain.

Citation: Brutcher RE et al. Compounded topical pain creams to treat localized chronic pain. Ann Intern Med. 2019;170(5):309-18.

Dr. Lambert is a hospital medicine clinician and addiction medicine specialist in the division of hospital medicine at Massachusetts General Hospital.

Background: Federal health system programs, including TRICARE for military personnel, spent $259 million in 2013 and $746 million in 2014 for compounded analgesic medications despite a dearth of efficacy data. The purpose of this trial was to evaluate the efficacy and functional impact of this class of medications for chronic localized pain.

The primary outcome was the average pain score at 1 month follow-up, based on self-recorded arithmetic mean pain scores in the preceding week. Secondary outcomes included mean worst pain over the past week, functional improvement (assessed by validated Short-Form 36 Health Survey scores), and satisfaction (measured on a 1 to 5 Likert scale) with the individual treatment regimen.

Patients had small improvements in average pain scores at 1 month in the compounded formulation and placebo subgroups in all pain type categories. No significant differences were noted in the average pain scores compared to baseline, functional improvement or satisfaction in the compounded formulation and placebo groups of the total cohort or in any of the subgroups.

Bottom line: Compounded topical analgesics are costly and ineffective in the treatment of all types of chronic localized pain.

Citation: Brutcher RE et al. Compounded topical pain creams to treat localized chronic pain. Ann Intern Med. 2019;170(5):309-18.

Dr. Lambert is a hospital medicine clinician and addiction medicine specialist in the division of hospital medicine at Massachusetts General Hospital.

Background: Federal health system programs, including TRICARE for military personnel, spent $259 million in 2013 and $746 million in 2014 for compounded analgesic medications despite a dearth of efficacy data. The purpose of this trial was to evaluate the efficacy and functional impact of this class of medications for chronic localized pain.

The primary outcome was the average pain score at 1 month follow-up, based on self-recorded arithmetic mean pain scores in the preceding week. Secondary outcomes included mean worst pain over the past week, functional improvement (assessed by validated Short-Form 36 Health Survey scores), and satisfaction (measured on a 1 to 5 Likert scale) with the individual treatment regimen.

Patients had small improvements in average pain scores at 1 month in the compounded formulation and placebo subgroups in all pain type categories. No significant differences were noted in the average pain scores compared to baseline, functional improvement or satisfaction in the compounded formulation and placebo groups of the total cohort or in any of the subgroups.

Bottom line: Compounded topical analgesics are costly and ineffective in the treatment of all types of chronic localized pain.

Citation: Brutcher RE et al. Compounded topical pain creams to treat localized chronic pain. Ann Intern Med. 2019;170(5):309-18.

Dr. Lambert is a hospital medicine clinician and addiction medicine specialist in the division of hospital medicine at Massachusetts General Hospital.

Older adults with COVID-19, the illness caused by the coronavirus, have several “atypical” symptoms, complicating efforts to ensure they get timely and appropriate treatment, according to physicians.

COVID-19 is typically signaled by three symptoms: a fever, an insistent cough, and shortness of breath. But older adults – the age group most at risk of severe complications or death from this condition – may have none of these characteristics.

Instead, seniors may seem “off” – not acting like themselves – early on after being infected by the coronavirus. They may sleep more than usual or stop eating. They may seem unusually apathetic or confused, losing orientation to their surroundings. They may become dizzy and fall. Sometimes, seniors stop speaking or simply collapse.

“With a lot of conditions, older adults don’t present in a typical way, and we’re seeing that with COVID-19 as well,” said Camille Vaughan, MD, section chief of geriatrics and gerontology at Emory University, Atlanta.

The reason has to do with how older bodies respond to illness and infection.

At advanced ages, “someone’s immune response may be blunted and their ability to regulate temperature may be altered,” said Dr. Joseph Ouslander, a professor of geriatric medicine at Florida Atlantic University in Boca Raton.

“Underlying chronic illnesses can mask or interfere with signs of infection,” he said. “Some older people, whether from age-related changes or previous neurologic issues such as a stroke, may have altered cough reflexes. Others with cognitive impairment may not be able to communicate their symptoms.”

Recognizing danger signs is important: If early signs of COVID-19 are missed, seniors may deteriorate before getting needed care. And people may go in and out of their homes without adequate protective measures, risking the spread of infection.

Quratulain Syed, MD, an Atlanta geriatrician, describes a man in his 80s whom she treated in mid-March. Over a period of days, this patient, who had heart disease, diabetes and moderate cognitive impairment, stopped walking and became incontinent and profoundly lethargic. But he didn’t have a fever or a cough. His only respiratory symptom: sneezing off and on.

The man’s elderly spouse called 911 twice. Both times, paramedics checked his vital signs and declared he was OK. After another worried call from the overwhelmed spouse, Dr. Syed insisted the patient be taken to the hospital, where he tested positive for COVID-19.

“I was quite concerned about the paramedics and health aides who’d been in the house and who hadn’t used PPE [personal protective equipment],” Dr. Syed said.

Dr. Sam Torbati, medical director of the emergency department at Cedars-Sinai Medical Center, Los Angeles, describes treating seniors who initially appear to be trauma patients but are found to have COVID-19.

“They get weak and dehydrated,” he said, “and when they stand to walk, they collapse and injure themselves badly.”

Dr. Torbati has seen older adults who are profoundly disoriented and unable to speak and who appear at first to have suffered strokes.

“When we test them, we discover that what’s producing these changes is a central nervous system effect of coronavirus,” he said.

Laura Perry, MD, of the University of California, San Francisco, saw a patient like this several weeks ago. The woman, in her 80s, had what seemed to be a cold before becoming very confused. In the hospital, she couldn’t identify where she was or stay awake during an examination. Dr. Perry diagnosed hypoactive delirium, an altered mental state in which people become inactive and drowsy. The patient tested positive for coronavirus and is still in the ICU.

Anthony Perry, MD, of the department of geriatric medicine at Rush University Medical Center in Chicago, tells of an 81-year-old woman with nausea, vomiting, and diarrhea who tested positive for COVID-19 in the emergency room. After receiving intravenous fluids, oxygen, and medication for her intestinal upset, she returned home after 2 days and is doing well.

Another 80-year-old Rush patient with similar symptoms – nausea and vomiting, but no cough, fever, or shortness of breath – is in intensive care after getting a positive COVID-19 test and due to be put on a ventilator. The difference? This patient is frail with “a lot of cardiovascular disease,” Dr. Perry said. Other than that, it’s not yet clear why some older patients do well while others do not.

So far, reports of cases like these have been anecdotal. But a few physicians are trying to gather more systematic information.

In Switzerland, Sylvain Nguyen, MD, a geriatrician at the University of Lausanne Hospital Center, put together a list of typical and atypical symptoms in older COVID-19 patients for a paper to be published in the Revue Médicale Suisse. Included on the atypical list are changes in a patient’s usual status, delirium, falls, fatigue, lethargy, low blood pressure, painful swallowing, fainting, diarrhea, nausea, vomiting, abdominal pain, and the loss of smell and taste.

Data come from hospitals and nursing homes in Switzerland, Italy, and France, Dr. Nguyen said in an email.

On the front lines, physicians need to make sure they carefully assess an older patient’s symptoms.

“While we have to have a high suspicion of COVID-19 because it’s so dangerous in the older population, there are many other things to consider,” said Kathleen Unroe, MD, a geriatrician at Indiana University, Indianapolis.

Seniors may also do poorly because their routines have changed. In nursing homes and most assisted living centers, activities have stopped and “residents are going to get weaker and more deconditioned because they’re not walking to and from the dining hall,” she said.

At home, isolated seniors may not be getting as much help with medication management or other essential needs from family members who are keeping their distance, other experts suggested. Or they may have become apathetic or depressed.

“I’d want to know ‘What’s the potential this person has had an exposure [to the coronavirus], especially in the last 2 weeks?’ ” said Dr. Vaughan of Emory. “Do they have home health personnel coming in? Have they gotten together with other family members? Are chronic conditions being controlled? Is there another diagnosis that seems more likely?”

“Someone may be just having a bad day. But if they’re not themselves for a couple of days, absolutely reach out to a primary care doctor or a local health system hotline to see if they meet the threshold for [coronavirus] testing,” Dr. Vaughan advised. “Be persistent. If you get a ‘no’ the first time and things aren’t improving, call back and ask again.”

Kaiser Health News (khn.org) is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Older adults with COVID-19, the illness caused by the coronavirus, have several “atypical” symptoms, complicating efforts to ensure they get timely and appropriate treatment, according to physicians.

COVID-19 is typically signaled by three symptoms: a fever, an insistent cough, and shortness of breath. But older adults – the age group most at risk of severe complications or death from this condition – may have none of these characteristics.

Instead, seniors may seem “off” – not acting like themselves – early on after being infected by the coronavirus. They may sleep more than usual or stop eating. They may seem unusually apathetic or confused, losing orientation to their surroundings. They may become dizzy and fall. Sometimes, seniors stop speaking or simply collapse.

“With a lot of conditions, older adults don’t present in a typical way, and we’re seeing that with COVID-19 as well,” said Camille Vaughan, MD, section chief of geriatrics and gerontology at Emory University, Atlanta.

The reason has to do with how older bodies respond to illness and infection.

At advanced ages, “someone’s immune response may be blunted and their ability to regulate temperature may be altered,” said Dr. Joseph Ouslander, a professor of geriatric medicine at Florida Atlantic University in Boca Raton.

“Underlying chronic illnesses can mask or interfere with signs of infection,” he said. “Some older people, whether from age-related changes or previous neurologic issues such as a stroke, may have altered cough reflexes. Others with cognitive impairment may not be able to communicate their symptoms.”

Recognizing danger signs is important: If early signs of COVID-19 are missed, seniors may deteriorate before getting needed care. And people may go in and out of their homes without adequate protective measures, risking the spread of infection.

Quratulain Syed, MD, an Atlanta geriatrician, describes a man in his 80s whom she treated in mid-March. Over a period of days, this patient, who had heart disease, diabetes and moderate cognitive impairment, stopped walking and became incontinent and profoundly lethargic. But he didn’t have a fever or a cough. His only respiratory symptom: sneezing off and on.

The man’s elderly spouse called 911 twice. Both times, paramedics checked his vital signs and declared he was OK. After another worried call from the overwhelmed spouse, Dr. Syed insisted the patient be taken to the hospital, where he tested positive for COVID-19.

“I was quite concerned about the paramedics and health aides who’d been in the house and who hadn’t used PPE [personal protective equipment],” Dr. Syed said.

Dr. Sam Torbati, medical director of the emergency department at Cedars-Sinai Medical Center, Los Angeles, describes treating seniors who initially appear to be trauma patients but are found to have COVID-19.

“They get weak and dehydrated,” he said, “and when they stand to walk, they collapse and injure themselves badly.”

Dr. Torbati has seen older adults who are profoundly disoriented and unable to speak and who appear at first to have suffered strokes.

“When we test them, we discover that what’s producing these changes is a central nervous system effect of coronavirus,” he said.

Laura Perry, MD, of the University of California, San Francisco, saw a patient like this several weeks ago. The woman, in her 80s, had what seemed to be a cold before becoming very confused. In the hospital, she couldn’t identify where she was or stay awake during an examination. Dr. Perry diagnosed hypoactive delirium, an altered mental state in which people become inactive and drowsy. The patient tested positive for coronavirus and is still in the ICU.

Anthony Perry, MD, of the department of geriatric medicine at Rush University Medical Center in Chicago, tells of an 81-year-old woman with nausea, vomiting, and diarrhea who tested positive for COVID-19 in the emergency room. After receiving intravenous fluids, oxygen, and medication for her intestinal upset, she returned home after 2 days and is doing well.

Another 80-year-old Rush patient with similar symptoms – nausea and vomiting, but no cough, fever, or shortness of breath – is in intensive care after getting a positive COVID-19 test and due to be put on a ventilator. The difference? This patient is frail with “a lot of cardiovascular disease,” Dr. Perry said. Other than that, it’s not yet clear why some older patients do well while others do not.

So far, reports of cases like these have been anecdotal. But a few physicians are trying to gather more systematic information.

In Switzerland, Sylvain Nguyen, MD, a geriatrician at the University of Lausanne Hospital Center, put together a list of typical and atypical symptoms in older COVID-19 patients for a paper to be published in the Revue Médicale Suisse. Included on the atypical list are changes in a patient’s usual status, delirium, falls, fatigue, lethargy, low blood pressure, painful swallowing, fainting, diarrhea, nausea, vomiting, abdominal pain, and the loss of smell and taste.

Data come from hospitals and nursing homes in Switzerland, Italy, and France, Dr. Nguyen said in an email.

On the front lines, physicians need to make sure they carefully assess an older patient’s symptoms.

“While we have to have a high suspicion of COVID-19 because it’s so dangerous in the older population, there are many other things to consider,” said Kathleen Unroe, MD, a geriatrician at Indiana University, Indianapolis.

Seniors may also do poorly because their routines have changed. In nursing homes and most assisted living centers, activities have stopped and “residents are going to get weaker and more deconditioned because they’re not walking to and from the dining hall,” she said.

At home, isolated seniors may not be getting as much help with medication management or other essential needs from family members who are keeping their distance, other experts suggested. Or they may have become apathetic or depressed.

“I’d want to know ‘What’s the potential this person has had an exposure [to the coronavirus], especially in the last 2 weeks?’ ” said Dr. Vaughan of Emory. “Do they have home health personnel coming in? Have they gotten together with other family members? Are chronic conditions being controlled? Is there another diagnosis that seems more likely?”

“Someone may be just having a bad day. But if they’re not themselves for a couple of days, absolutely reach out to a primary care doctor or a local health system hotline to see if they meet the threshold for [coronavirus] testing,” Dr. Vaughan advised. “Be persistent. If you get a ‘no’ the first time and things aren’t improving, call back and ask again.”

Kaiser Health News (khn.org) is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Older adults with COVID-19, the illness caused by the coronavirus, have several “atypical” symptoms, complicating efforts to ensure they get timely and appropriate treatment, according to physicians.

COVID-19 is typically signaled by three symptoms: a fever, an insistent cough, and shortness of breath. But older adults – the age group most at risk of severe complications or death from this condition – may have none of these characteristics.

Instead, seniors may seem “off” – not acting like themselves – early on after being infected by the coronavirus. They may sleep more than usual or stop eating. They may seem unusually apathetic or confused, losing orientation to their surroundings. They may become dizzy and fall. Sometimes, seniors stop speaking or simply collapse.

“With a lot of conditions, older adults don’t present in a typical way, and we’re seeing that with COVID-19 as well,” said Camille Vaughan, MD, section chief of geriatrics and gerontology at Emory University, Atlanta.

The reason has to do with how older bodies respond to illness and infection.

At advanced ages, “someone’s immune response may be blunted and their ability to regulate temperature may be altered,” said Dr. Joseph Ouslander, a professor of geriatric medicine at Florida Atlantic University in Boca Raton.

“Underlying chronic illnesses can mask or interfere with signs of infection,” he said. “Some older people, whether from age-related changes or previous neurologic issues such as a stroke, may have altered cough reflexes. Others with cognitive impairment may not be able to communicate their symptoms.”

Recognizing danger signs is important: If early signs of COVID-19 are missed, seniors may deteriorate before getting needed care. And people may go in and out of their homes without adequate protective measures, risking the spread of infection.

Quratulain Syed, MD, an Atlanta geriatrician, describes a man in his 80s whom she treated in mid-March. Over a period of days, this patient, who had heart disease, diabetes and moderate cognitive impairment, stopped walking and became incontinent and profoundly lethargic. But he didn’t have a fever or a cough. His only respiratory symptom: sneezing off and on.

The man’s elderly spouse called 911 twice. Both times, paramedics checked his vital signs and declared he was OK. After another worried call from the overwhelmed spouse, Dr. Syed insisted the patient be taken to the hospital, where he tested positive for COVID-19.

“I was quite concerned about the paramedics and health aides who’d been in the house and who hadn’t used PPE [personal protective equipment],” Dr. Syed said.

Dr. Sam Torbati, medical director of the emergency department at Cedars-Sinai Medical Center, Los Angeles, describes treating seniors who initially appear to be trauma patients but are found to have COVID-19.

“They get weak and dehydrated,” he said, “and when they stand to walk, they collapse and injure themselves badly.”

Dr. Torbati has seen older adults who are profoundly disoriented and unable to speak and who appear at first to have suffered strokes.

“When we test them, we discover that what’s producing these changes is a central nervous system effect of coronavirus,” he said.

Laura Perry, MD, of the University of California, San Francisco, saw a patient like this several weeks ago. The woman, in her 80s, had what seemed to be a cold before becoming very confused. In the hospital, she couldn’t identify where she was or stay awake during an examination. Dr. Perry diagnosed hypoactive delirium, an altered mental state in which people become inactive and drowsy. The patient tested positive for coronavirus and is still in the ICU.

Anthony Perry, MD, of the department of geriatric medicine at Rush University Medical Center in Chicago, tells of an 81-year-old woman with nausea, vomiting, and diarrhea who tested positive for COVID-19 in the emergency room. After receiving intravenous fluids, oxygen, and medication for her intestinal upset, she returned home after 2 days and is doing well.

Another 80-year-old Rush patient with similar symptoms – nausea and vomiting, but no cough, fever, or shortness of breath – is in intensive care after getting a positive COVID-19 test and due to be put on a ventilator. The difference? This patient is frail with “a lot of cardiovascular disease,” Dr. Perry said. Other than that, it’s not yet clear why some older patients do well while others do not.

So far, reports of cases like these have been anecdotal. But a few physicians are trying to gather more systematic information.

In Switzerland, Sylvain Nguyen, MD, a geriatrician at the University of Lausanne Hospital Center, put together a list of typical and atypical symptoms in older COVID-19 patients for a paper to be published in the Revue Médicale Suisse. Included on the atypical list are changes in a patient’s usual status, delirium, falls, fatigue, lethargy, low blood pressure, painful swallowing, fainting, diarrhea, nausea, vomiting, abdominal pain, and the loss of smell and taste.

Data come from hospitals and nursing homes in Switzerland, Italy, and France, Dr. Nguyen said in an email.

On the front lines, physicians need to make sure they carefully assess an older patient’s symptoms.

“While we have to have a high suspicion of COVID-19 because it’s so dangerous in the older population, there are many other things to consider,” said Kathleen Unroe, MD, a geriatrician at Indiana University, Indianapolis.

Seniors may also do poorly because their routines have changed. In nursing homes and most assisted living centers, activities have stopped and “residents are going to get weaker and more deconditioned because they’re not walking to and from the dining hall,” she said.

At home, isolated seniors may not be getting as much help with medication management or other essential needs from family members who are keeping their distance, other experts suggested. Or they may have become apathetic or depressed.

“I’d want to know ‘What’s the potential this person has had an exposure [to the coronavirus], especially in the last 2 weeks?’ ” said Dr. Vaughan of Emory. “Do they have home health personnel coming in? Have they gotten together with other family members? Are chronic conditions being controlled? Is there another diagnosis that seems more likely?”

“Someone may be just having a bad day. But if they’re not themselves for a couple of days, absolutely reach out to a primary care doctor or a local health system hotline to see if they meet the threshold for [coronavirus] testing,” Dr. Vaughan advised. “Be persistent. If you get a ‘no’ the first time and things aren’t improving, call back and ask again.”

Kaiser Health News (khn.org) is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

Physicians in New York, which still leads the nation in reported COVID-19 cases, are reporting significantly more acute, large vessel strokes in young adults infected with COVID-19.

In a rapid communication to be published online April 29 in the New England Journal of Medicine, investigators led by Thomas Oxley, MD, PhD, of the department of neurosurgery at Mount Sinai Health System, reported five cases of large vessel stroke over a 2-week period in COVID-19 patients under age 50 years. This represents a sevenfold increase in what would normally be expected.

The five cases had either no, or mild, COVID-19 symptoms.

“It’s been surprising to learn that the virus appears to cause disease through a process of blood clotting,” Dr. Oxley said in an interview.

The message for neurologists and other physicians is “we’re learning that this can disproportionally affect large vessels more than small vessels in terms of presentation of stroke,” he said.

Inflammation in the blood vessel walls may be driving thrombosis formation, Dr. Oxley added. This report joins other research pointing to this emerging phenomenon.

Recently, investigators in the Netherlands found a “remarkably high” 31% rate of thrombotic complications among 184 critical care patients with COVID-19 pneumonia.

Dr. Oxley and colleagues also suggested that, since the onset of the pandemic, fewer patients may be calling emergency services when they experience signs of a stroke. The physicians noted that two of the five cases in the report delayed calling an ambulance.

“I understand why people do not want to leave the household. I think people are more willing to ignore other [non–COVID-19] symptoms in this environment,” he said.

As previously reported, physicians in hospitals across the United States and elsewhere have reported a significant drop in stroke patients since the COVID-19 pandemic took hold, which suggests that patients may indeed be foregoing emergency care.

The observations from Dr. Oxley and colleagues call for greater awareness of the association between COVID-19 and large vessel strokes in this age group, they add.

One patient in the case series died, one remains hospitalized, two are undergoing rehabilitation, and one was discharged home as of April 24.

Dr. Oxley and colleagues dedicated their report to “our inspiring colleague Gary Sclar, MD, a stroke physician who succumbed to COVID-19 while caring for his patients.”

Dr. Oxley has disclosed no relevant financial relationships.

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

Physicians in New York, which still leads the nation in reported COVID-19 cases, are reporting significantly more acute, large vessel strokes in young adults infected with COVID-19.

In a rapid communication to be published online April 29 in the New England Journal of Medicine, investigators led by Thomas Oxley, MD, PhD, of the department of neurosurgery at Mount Sinai Health System, reported five cases of large vessel stroke over a 2-week period in COVID-19 patients under age 50 years. This represents a sevenfold increase in what would normally be expected.

The five cases had either no, or mild, COVID-19 symptoms.

“It’s been surprising to learn that the virus appears to cause disease through a process of blood clotting,” Dr. Oxley said in an interview.

The message for neurologists and other physicians is “we’re learning that this can disproportionally affect large vessels more than small vessels in terms of presentation of stroke,” he said.

Inflammation in the blood vessel walls may be driving thrombosis formation, Dr. Oxley added. This report joins other research pointing to this emerging phenomenon.

Recently, investigators in the Netherlands found a “remarkably high” 31% rate of thrombotic complications among 184 critical care patients with COVID-19 pneumonia.

Dr. Oxley and colleagues also suggested that, since the onset of the pandemic, fewer patients may be calling emergency services when they experience signs of a stroke. The physicians noted that two of the five cases in the report delayed calling an ambulance.

“I understand why people do not want to leave the household. I think people are more willing to ignore other [non–COVID-19] symptoms in this environment,” he said.

As previously reported, physicians in hospitals across the United States and elsewhere have reported a significant drop in stroke patients since the COVID-19 pandemic took hold, which suggests that patients may indeed be foregoing emergency care.

The observations from Dr. Oxley and colleagues call for greater awareness of the association between COVID-19 and large vessel strokes in this age group, they add.

One patient in the case series died, one remains hospitalized, two are undergoing rehabilitation, and one was discharged home as of April 24.

Dr. Oxley and colleagues dedicated their report to “our inspiring colleague Gary Sclar, MD, a stroke physician who succumbed to COVID-19 while caring for his patients.”

Dr. Oxley has disclosed no relevant financial relationships.

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

Physicians in New York, which still leads the nation in reported COVID-19 cases, are reporting significantly more acute, large vessel strokes in young adults infected with COVID-19.

In a rapid communication to be published online April 29 in the New England Journal of Medicine, investigators led by Thomas Oxley, MD, PhD, of the department of neurosurgery at Mount Sinai Health System, reported five cases of large vessel stroke over a 2-week period in COVID-19 patients under age 50 years. This represents a sevenfold increase in what would normally be expected.

The five cases had either no, or mild, COVID-19 symptoms.

“It’s been surprising to learn that the virus appears to cause disease through a process of blood clotting,” Dr. Oxley said in an interview.

The message for neurologists and other physicians is “we’re learning that this can disproportionally affect large vessels more than small vessels in terms of presentation of stroke,” he said.

Inflammation in the blood vessel walls may be driving thrombosis formation, Dr. Oxley added. This report joins other research pointing to this emerging phenomenon.

Recently, investigators in the Netherlands found a “remarkably high” 31% rate of thrombotic complications among 184 critical care patients with COVID-19 pneumonia.

Dr. Oxley and colleagues also suggested that, since the onset of the pandemic, fewer patients may be calling emergency services when they experience signs of a stroke. The physicians noted that two of the five cases in the report delayed calling an ambulance.

“I understand why people do not want to leave the household. I think people are more willing to ignore other [non–COVID-19] symptoms in this environment,” he said.

As previously reported, physicians in hospitals across the United States and elsewhere have reported a significant drop in stroke patients since the COVID-19 pandemic took hold, which suggests that patients may indeed be foregoing emergency care.

The observations from Dr. Oxley and colleagues call for greater awareness of the association between COVID-19 and large vessel strokes in this age group, they add.

One patient in the case series died, one remains hospitalized, two are undergoing rehabilitation, and one was discharged home as of April 24.

Dr. Oxley and colleagues dedicated their report to “our inspiring colleague Gary Sclar, MD, a stroke physician who succumbed to COVID-19 while caring for his patients.”

Dr. Oxley has disclosed no relevant financial relationships.

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

Brant Oliver, PhD, MS, MPH, APRN-BC, is a health care improvement and implementation scientist, educator, and board-certified family and psychiatric nurse practitioner (FNP-BC, PMHNP-BC). Dr. Oliver's work focuses on applied health care improvement science research, with a focus on "3C" (complex, costly, and chronic) conditions including MS, IBD, CF, RA, and others; coproduction; learning health systems; and shared decision making. He is Associate Professor at the Geisel School of Medicine at Dartmouth and also has been in clinical practice since 2003, working primarily as a certified MS specialist (MSCN) and a MS neurobehavioral nurse practitioner.  

Which patient-reported outcomes (PROs) are commonly assessed in the care of patients with multiple sclerosis (MS)?

BRANT OLIVER, PhD: The current reality is that PROs are not being used routinely in MS clinical care in most settings. They are most commonly being used in research settings, either as part of clinical trials of new treatments, or in epidemiologic studies looking at the prevalence, incidence, and severity of certain symptoms or functional impairments in MS at the population level. A good example is the NARCOMS registry, which has been used to conduct  high-quality epidemiologic studies of MS-related symptoms using self-report questionnaires.

We are starting to see some use of MS PROs in select clinical settings. Oftentimes these are measures of highly prevalent comorbid conditions that have an impact on quality of life, treatment adherence (depression severity and anxiety), and self-efficacy, which is a measure of perceived coping ability related to self-management of a chronic illness. Also, measures of patient experience are being employed in hospital-based clinics, such as the CG-CAHPS satisfaction measures.

The PROMIS (Patient-Reported Outcomes Measurement Information System) battery is a promising set of PRO measures that are being utilized across a number of conditions and that contain some MS-specific measures, such as the Fatigue MS measure. Fatigue is the most common and disabling symptom in MS, so having a good measure of fatigue is of critical importance. Having a sense of a patient’s experience with fatigue over time can also be very helpful from a clinical perspective. The PROMIS measure performs much better than its predecessor, the Modified Fatigue Impact Scale (MFIS). Another strength of the PROMIS measures is that they tend to do well correlating with other conditions. In certain research and improvement settings, PROMIS can help us understand the burden a particular disease or population places on total health system resources. For example, is fatigue burden in MS similar in severity to that in another 3C condition, such as inflammatory bowel disease?

There are other PRO measures that have not been used in MS but which I think we will see used in the future. One of these is called Collaborate, which falls into the category of patient-reported experience measures (PREMs). Collaborate measures the degree of shared decision-making that occurs in a clinical encounter, which becomes especially important as the complexity of disease-modifying treatment decisions increases as more disease-modifying therapies are introduced, each with their own profile of risks and benefits. I anticipate that the ability of clinics to facilitate effective shared decision-making will be of increasing interest to clinicians, patients, and also payers in the future.

What are some of the potential benefits of using PRO measures in terms of clinician/patient communication and clinical decision-making?

BRANT OLIVER, PhD: I think the most important benefit of measuring PROs is that it can make care more patient-centered. The big push for PROs in the first place was to incorporate more of the patient’s voice into their own care. Standard clinical measures, such as magnetic resonance imaging (MRI) or relapse rates, can be very precise and provide a good clinical picture of how the disease is behaving. But if we rely solely on that kind of information, we can lose sight of the person who is experiencing the disease.

PROs, be they just regular PROs (instruments that gather qualitative and/or quantitative patient-reported information) or PROMs (validated and standardized PRO measures) or PREMs (standardized and validated patient-reported experience measures), all aim to improve the ability to get a better story of the person who's experiencing the illness and how that condition affects them. We can also gain insight on what's most important to them regarding how their illness is managed, and what their experience of care is.

Sometimes the PRO picture and the clinical picture don't necessarily align. I'll tell a story about one a person, who's given me permission to share the story. She is an established professional, and her PRO measures concerning her quality of life, support from her workplace environment, and her ability to function in society are very high. She's very high functioning according to the PRO picture.  However,  her clinical measures suggest that she is significantly impaired. Her MRI burden is quite high, and her disability due to the MS, her EDSS (Expanded Disability Status Scale), is also quite high. So there are 2 very different stories provided by 2 different sets of data. The inclusion of PROs data, in connection with clinical data, can provide a more holistic view of this person, who is functioning well despite significant disease burden.

As a clinician working with patients with MS, this gives me much more to work with in trying to help people, not only treating the disease, but also trying to see where the person is most in need of help. A person could be very well controlled on MRI in terms of relapse rate, but have fatigue severity that is through the roof. If I weren't paying closer attention to that with a validated scale that measures fatigue severity over time, like the PROMIS Fatigue MS, I may not have a sense of how well treatment is helping that person's fatigue longitudinally, beyond what I can glean from the history and clinical examination.

PROs can also be helpful in terms of conditions that are harder to quantify. Depression is a significant cause of disability and a significant factor contributing to poor treatment adherence in MS. Also, the suicide rate in persons with MS is much higher than that in the general population. But there is no blood test for depression severity, and oftentimes a patient’s report on exam can be incomplete or misleading. Accompanying the mental status exam and the clinical evaluation with a validated depression severity measure (such as the PHQ9 [Patient Health Questionnaire-9], CES-D [Center for Epidemiologic Studies Depression Scale], or others) can help to determine whether treatments are having an initial effect, and this can also help with self-monitoring and treatment adherence.  

That brings us to the second area where PROs show real promise in MS care: the learning health system (LHS) approach, which uses feed forward information to either predict the needs of people before they come to the office or optimize decision-making at the point of care (as discussed in our review article published in JCOM).¹

PROs can play a significant role in the LHS approach in 2 ways. For example, if I have a good sense before a visit that the person has stable symptoms but is having a lot of trouble coping with MS, that may change how I allocate resources and focus the time at the visit to target the primary concern of the person before the visit even occurs. Over time I'd be able to monitor if those coping scores increase in response to the work we’re doing with the person.

The second part of this approach is a feedback mechanism. These measures can be aggregated at the population level and fed back to clinical MS centers to help clinicians who are trying to improve overall population health outcomes of people with MS to see how well they're doing on things like fatigue management, depression management, coping ability, and pain control, which can't be tested for with biologic methods. So in addition to looking at the MRI scan trends across the population and relapse rate annualized for the population over time, I'd also be able to see fatigue severity and depression severity at a clinic population level and assess the change in these severity levels over time, which I could then use to inform efforts to change how my system (clinic) provides MS care.

This capability of PROs could be of significant interest to payers, especially those who are looking to optimize the value of care that is being provided, given the high cost of MS care. MS treatments are very expensive, and MS care is multidisciplinary and requires a lot of resources. Payers, I think, will have an increasing interest in assessing the value of high-cost care. PROs could help to demonstrate that value, especially if they can help quantify that outcomes can be improved over time at the population level.

The third area where PROs are beneficial is population health research, especially in terms of the major improvement movements going on in the country, such as those advocated for by the Institute for Healthcare Improvement via the Triple Aim: improve population health outcomes, improve the experience of care, and minimize per capita cost. PROs can really help with the first 2 of those Triple Aim categories.

What are some of the factors that limit the use of PRO measures in MS research and clinical practice?

BRANT OLIVER, PhD: In our JCOM paper,¹ we outlined major barriers or constraints or challenges to implementing PRO measures. One is time and technology in clinical care. It's busy. It's fast. A PRO measure requires patients to complete a questionnaire. And to do that, you need some time and space during the clinical visit, or before the visit, to collect this data. In the absence of appropriate technology, this is done using paper-based methods, which can be challenging. Technology can help. Examples include smart phone app-based collection systems, tablet PCs, or an online mechanism. But there are barriers to technology, too. Is the technology good enough? Is the interface with the people using it working well? Do you have an equal amount of access to and understanding of the technology from the people across your population? Is it only being used by a certain subset that is wealthier and more educated, or maybe who has English as a first language? Such constraints can be overcome, but they’re present in any situation where you are gathering PRO data.

Software constraints also extend to the electronic health record (EHR) capability of the clinics. If you can collect PRO data, does the EHR have the capability to present that data in a useful way during a 20- or 30-minute clinical visit? In other words, does it improve the quality of the visit, or does it generate just one more distraction during the visit? Some approaches, such as feed forward dashboards, provide easy visual displays that can quickly and easily add information at the point of care and can get around this limitation. However, a lot of MS care centers in private practice settings may not have the informatics capability of a large academic center.

 Academic centers often have more EHR capability, but can also  move much slower in implementation than more nimble private practice or community clinics. With many competing demands, it can sometimes take months to build one of these surveys into an EHR, for a task that takes just a day or so. But because other departments are in the queue for these changes, implementation often takes longer than we would intuitively think.

A second barrier is the burden on the individuals themselves. As much as we feel that PROs can make a difference, and the growing literature suggests that they really can, this is counterbalanced with the burden they may place on the patient. For example, a person may arrive at a clinic visit already with a lot on their mind, and then they get a questionnaire to complete in the waiting room before their visit (or perhaps they get asked to do it at home before the visit). The patient, rather than perceiving this as beneficial, may instead perceive it as an extra task or stressor. Explaining the purpose of the PRO measures, encouraging their use, and then actually using the results meaningfully during the visit can substantially improve their perceived value.

It’s important to limit the total amount of PROs used. In research, as well as in clinical settings, too many measures can lead to too little data. It's similar to an overly complex treatment plan: the chance that a person will adhere to all of it decreases with each level of complexity added. This can lead to decreased engagement by patients, and gradually they'll move away from participating in the PROs in general. Research and clinical efforts around PROs strive to get to a parsimonious set of critical measures, which will minimize the burden, but maximize the potential benefit.

 A third challenge is interpretability. This gets into the psychometric properties of the PRO measures and setting appropriate clinical thresholds for what constitutes a “positive” or “actionable” result. What is a clinically significant level of fatigue severity on the PROMIS MS Fatigue? We know that the mean range of that instrument is somewhere between 50 and 60. Does that mean that scores above 60 suggest higher than average fatigue levels, or is it more complicated than that? In many cases, the instruments don't have extensive population level research for the populations in which they are used. Setting clinical thresholds can be difficult, and I suspect that this will be a major area of research in the coming years.

Another example is setting appropriate depression thresholds. We know that on the CES-D, for example, the positive threshold for active depression in a patient with MS may be different from that in a patient without MS, because fatigue is a contributing factor to the neurovegetative symptoms that are scored on the CES-D.

So even if we can incorporate PROs into general practice and minimize burden, we also have to pay attention to factors that limit their interpretability and employ them in a way whereby they provide clinically meaningful results that can help inform care. The good news is,  for many PROs, even with these limitations, this can be done.

Following directly from this is error risk. Many PRO measures were designed for large-sample epidemiologic research, not for a smaller sample clinical practice, which can lead to a higher error risk, especially when following single individuals over time. Adjustments in how these scales are interpreted are required in many cases.

The limitations of many of the respondents completing questionnaires needs to be taken into account. Fatigue and cognitive impairment are very common in MS. Respondents may be selecting answers that are not entirely accurate if they're getting fatigued while doing the surveys, or if they have a comprehension deficit or a short-term memory deficit.

            A final challenge is demonstrating, just like any treatment or assessment approach, that the benefit outweighs the burden. PRO measures that are fairly reliable, validated, and quick and easy to complete suddenly become quite valuable because their benefit far outweighs the potential constraints. I think as PROs and the ways of assessing them continue to develop, that will become a bigger issue. The question will be, okay, you can do this, but what is the value added by doing this? That added value could be demonstrated in terms of better clinical outcomes, reduced costs, reduced hospitalizations, better treatment adherence, and so on.

How do you see the use of patient-reported outcomes in MS care evolving over time?

BRANT OLIVER, PhD: I tend to be optimistic regarding PROs. I think they will become part of the new reality, especially in LHS-oriented models of care. As mentioned, LHSs use feed forward data to predict the needs of people or optimize shared decision-making. I think we're going to see more shared decision-making rather than less over time in complex chronic illnesses care.

In environments where there's an increasing focus on value for high-cost, such as complex chronic conditions like MS and inflammatory bowel disease, systems will have to justify the high cost of treatment. PROs will be a critical piece in making that value assessment, especially since that value assessment is coming from the voice of patients rather than only from clinicians or other stakeholders. Arguably, patients may be able to contribute the most to making the value proposition because it is their outcomes and their experiences that matter to payers. Because experience matters (and not just outcomes), I think we'll see more PREMs used over time, including in MS.

I also think over time we'll see studies working to optimize PROs in the clinical environment and for improvement and research. An early example of that is the MS Continuous Quality Improvement (MS-CQI) Collaborative. It is a prospective randomized multicenter study using patient-reported and clinical data in a LHS approach to study population health outcomes and the effect of quality improvement interventions on those outcomes. It's also optimizing how these PRO measures are actually used at the point of care. Studies like MS-CQI will help to better articulate how, when, and for what purpose PROs should best be used and also when they should be avoided.

I think over time the predictive analytics component of PROs will be emphasized. There is a big push in the MS field in developing biomarkers to help predict disease progression over time. From the predictive analytics or machine learning perspective, imagine a situation where PROs could be used to predict a person's trajectory over time: if they were more likely to be lost to follow-up, to be hospitalized, or to have a relapse in the next year or 2. Reliable PROs generating population health data  at scale can inform the development of risk and outcome predictive models.  

Dr. Oliver discloses that he has received research grant support (MS-CQI research study mentioned in interview). He is the principal investigator and developer of the MS-CQI study, which is grant funded by Biogen under a Sponsored Research Agreement.

Brant Oliver, PhD, MS, MPH, APRN-BC, is a health care improvement and implementation scientist, educator, and board-certified family and psychiatric nurse practitioner (FNP-BC, PMHNP-BC). Dr. Oliver's work focuses on applied health care improvement science research, with a focus on "3C" (complex, costly, and chronic) conditions including MS, IBD, CF, RA, and others; coproduction; learning health systems; and shared decision making. He is Associate Professor at the Geisel School of Medicine at Dartmouth and also has been in clinical practice since 2003, working primarily as a certified MS specialist (MSCN) and a MS neurobehavioral nurse practitioner.  

Which patient-reported outcomes (PROs) are commonly assessed in the care of patients with multiple sclerosis (MS)?

BRANT OLIVER, PhD: The current reality is that PROs are not being used routinely in MS clinical care in most settings. They are most commonly being used in research settings, either as part of clinical trials of new treatments, or in epidemiologic studies looking at the prevalence, incidence, and severity of certain symptoms or functional impairments in MS at the population level. A good example is the NARCOMS registry, which has been used to conduct  high-quality epidemiologic studies of MS-related symptoms using self-report questionnaires.

We are starting to see some use of MS PROs in select clinical settings. Oftentimes these are measures of highly prevalent comorbid conditions that have an impact on quality of life, treatment adherence (depression severity and anxiety), and self-efficacy, which is a measure of perceived coping ability related to self-management of a chronic illness. Also, measures of patient experience are being employed in hospital-based clinics, such as the CG-CAHPS satisfaction measures.

The PROMIS (Patient-Reported Outcomes Measurement Information System) battery is a promising set of PRO measures that are being utilized across a number of conditions and that contain some MS-specific measures, such as the Fatigue MS measure. Fatigue is the most common and disabling symptom in MS, so having a good measure of fatigue is of critical importance. Having a sense of a patient’s experience with fatigue over time can also be very helpful from a clinical perspective. The PROMIS measure performs much better than its predecessor, the Modified Fatigue Impact Scale (MFIS). Another strength of the PROMIS measures is that they tend to do well correlating with other conditions. In certain research and improvement settings, PROMIS can help us understand the burden a particular disease or population places on total health system resources. For example, is fatigue burden in MS similar in severity to that in another 3C condition, such as inflammatory bowel disease?

There are other PRO measures that have not been used in MS but which I think we will see used in the future. One of these is called Collaborate, which falls into the category of patient-reported experience measures (PREMs). Collaborate measures the degree of shared decision-making that occurs in a clinical encounter, which becomes especially important as the complexity of disease-modifying treatment decisions increases as more disease-modifying therapies are introduced, each with their own profile of risks and benefits. I anticipate that the ability of clinics to facilitate effective shared decision-making will be of increasing interest to clinicians, patients, and also payers in the future.

What are some of the potential benefits of using PRO measures in terms of clinician/patient communication and clinical decision-making?

BRANT OLIVER, PhD: I think the most important benefit of measuring PROs is that it can make care more patient-centered. The big push for PROs in the first place was to incorporate more of the patient’s voice into their own care. Standard clinical measures, such as magnetic resonance imaging (MRI) or relapse rates, can be very precise and provide a good clinical picture of how the disease is behaving. But if we rely solely on that kind of information, we can lose sight of the person who is experiencing the disease.

PROs, be they just regular PROs (instruments that gather qualitative and/or quantitative patient-reported information) or PROMs (validated and standardized PRO measures) or PREMs (standardized and validated patient-reported experience measures), all aim to improve the ability to get a better story of the person who's experiencing the illness and how that condition affects them. We can also gain insight on what's most important to them regarding how their illness is managed, and what their experience of care is.

Sometimes the PRO picture and the clinical picture don't necessarily align. I'll tell a story about one a person, who's given me permission to share the story. She is an established professional, and her PRO measures concerning her quality of life, support from her workplace environment, and her ability to function in society are very high. She's very high functioning according to the PRO picture.  However,  her clinical measures suggest that she is significantly impaired. Her MRI burden is quite high, and her disability due to the MS, her EDSS (Expanded Disability Status Scale), is also quite high. So there are 2 very different stories provided by 2 different sets of data. The inclusion of PROs data, in connection with clinical data, can provide a more holistic view of this person, who is functioning well despite significant disease burden.

As a clinician working with patients with MS, this gives me much more to work with in trying to help people, not only treating the disease, but also trying to see where the person is most in need of help. A person could be very well controlled on MRI in terms of relapse rate, but have fatigue severity that is through the roof. If I weren't paying closer attention to that with a validated scale that measures fatigue severity over time, like the PROMIS Fatigue MS, I may not have a sense of how well treatment is helping that person's fatigue longitudinally, beyond what I can glean from the history and clinical examination.

PROs can also be helpful in terms of conditions that are harder to quantify. Depression is a significant cause of disability and a significant factor contributing to poor treatment adherence in MS. Also, the suicide rate in persons with MS is much higher than that in the general population. But there is no blood test for depression severity, and oftentimes a patient’s report on exam can be incomplete or misleading. Accompanying the mental status exam and the clinical evaluation with a validated depression severity measure (such as the PHQ9 [Patient Health Questionnaire-9], CES-D [Center for Epidemiologic Studies Depression Scale], or others) can help to determine whether treatments are having an initial effect, and this can also help with self-monitoring and treatment adherence.  

That brings us to the second area where PROs show real promise in MS care: the learning health system (LHS) approach, which uses feed forward information to either predict the needs of people before they come to the office or optimize decision-making at the point of care (as discussed in our review article published in JCOM).¹

PROs can play a significant role in the LHS approach in 2 ways. For example, if I have a good sense before a visit that the person has stable symptoms but is having a lot of trouble coping with MS, that may change how I allocate resources and focus the time at the visit to target the primary concern of the person before the visit even occurs. Over time I'd be able to monitor if those coping scores increase in response to the work we’re doing with the person.

The second part of this approach is a feedback mechanism. These measures can be aggregated at the population level and fed back to clinical MS centers to help clinicians who are trying to improve overall population health outcomes of people with MS to see how well they're doing on things like fatigue management, depression management, coping ability, and pain control, which can't be tested for with biologic methods. So in addition to looking at the MRI scan trends across the population and relapse rate annualized for the population over time, I'd also be able to see fatigue severity and depression severity at a clinic population level and assess the change in these severity levels over time, which I could then use to inform efforts to change how my system (clinic) provides MS care.

This capability of PROs could be of significant interest to payers, especially those who are looking to optimize the value of care that is being provided, given the high cost of MS care. MS treatments are very expensive, and MS care is multidisciplinary and requires a lot of resources. Payers, I think, will have an increasing interest in assessing the value of high-cost care. PROs could help to demonstrate that value, especially if they can help quantify that outcomes can be improved over time at the population level.

The third area where PROs are beneficial is population health research, especially in terms of the major improvement movements going on in the country, such as those advocated for by the Institute for Healthcare Improvement via the Triple Aim: improve population health outcomes, improve the experience of care, and minimize per capita cost. PROs can really help with the first 2 of those Triple Aim categories.

What are some of the factors that limit the use of PRO measures in MS research and clinical practice?

BRANT OLIVER, PhD: In our JCOM paper,¹ we outlined major barriers or constraints or challenges to implementing PRO measures. One is time and technology in clinical care. It's busy. It's fast. A PRO measure requires patients to complete a questionnaire. And to do that, you need some time and space during the clinical visit, or before the visit, to collect this data. In the absence of appropriate technology, this is done using paper-based methods, which can be challenging. Technology can help. Examples include smart phone app-based collection systems, tablet PCs, or an online mechanism. But there are barriers to technology, too. Is the technology good enough? Is the interface with the people using it working well? Do you have an equal amount of access to and understanding of the technology from the people across your population? Is it only being used by a certain subset that is wealthier and more educated, or maybe who has English as a first language? Such constraints can be overcome, but they’re present in any situation where you are gathering PRO data.

Software constraints also extend to the electronic health record (EHR) capability of the clinics. If you can collect PRO data, does the EHR have the capability to present that data in a useful way during a 20- or 30-minute clinical visit? In other words, does it improve the quality of the visit, or does it generate just one more distraction during the visit? Some approaches, such as feed forward dashboards, provide easy visual displays that can quickly and easily add information at the point of care and can get around this limitation. However, a lot of MS care centers in private practice settings may not have the informatics capability of a large academic center.

 Academic centers often have more EHR capability, but can also  move much slower in implementation than more nimble private practice or community clinics. With many competing demands, it can sometimes take months to build one of these surveys into an EHR, for a task that takes just a day or so. But because other departments are in the queue for these changes, implementation often takes longer than we would intuitively think.

A second barrier is the burden on the individuals themselves. As much as we feel that PROs can make a difference, and the growing literature suggests that they really can, this is counterbalanced with the burden they may place on the patient. For example, a person may arrive at a clinic visit already with a lot on their mind, and then they get a questionnaire to complete in the waiting room before their visit (or perhaps they get asked to do it at home before the visit). The patient, rather than perceiving this as beneficial, may instead perceive it as an extra task or stressor. Explaining the purpose of the PRO measures, encouraging their use, and then actually using the results meaningfully during the visit can substantially improve their perceived value.

It’s important to limit the total amount of PROs used. In research, as well as in clinical settings, too many measures can lead to too little data. It's similar to an overly complex treatment plan: the chance that a person will adhere to all of it decreases with each level of complexity added. This can lead to decreased engagement by patients, and gradually they'll move away from participating in the PROs in general. Research and clinical efforts around PROs strive to get to a parsimonious set of critical measures, which will minimize the burden, but maximize the potential benefit.

 A third challenge is interpretability. This gets into the psychometric properties of the PRO measures and setting appropriate clinical thresholds for what constitutes a “positive” or “actionable” result. What is a clinically significant level of fatigue severity on the PROMIS MS Fatigue? We know that the mean range of that instrument is somewhere between 50 and 60. Does that mean that scores above 60 suggest higher than average fatigue levels, or is it more complicated than that? In many cases, the instruments don't have extensive population level research for the populations in which they are used. Setting clinical thresholds can be difficult, and I suspect that this will be a major area of research in the coming years.

Another example is setting appropriate depression thresholds. We know that on the CES-D, for example, the positive threshold for active depression in a patient with MS may be different from that in a patient without MS, because fatigue is a contributing factor to the neurovegetative symptoms that are scored on the CES-D.

So even if we can incorporate PROs into general practice and minimize burden, we also have to pay attention to factors that limit their interpretability and employ them in a way whereby they provide clinically meaningful results that can help inform care. The good news is,  for many PROs, even with these limitations, this can be done.

Following directly from this is error risk. Many PRO measures were designed for large-sample epidemiologic research, not for a smaller sample clinical practice, which can lead to a higher error risk, especially when following single individuals over time. Adjustments in how these scales are interpreted are required in many cases.

The limitations of many of the respondents completing questionnaires needs to be taken into account. Fatigue and cognitive impairment are very common in MS. Respondents may be selecting answers that are not entirely accurate if they're getting fatigued while doing the surveys, or if they have a comprehension deficit or a short-term memory deficit.

            A final challenge is demonstrating, just like any treatment or assessment approach, that the benefit outweighs the burden. PRO measures that are fairly reliable, validated, and quick and easy to complete suddenly become quite valuable because their benefit far outweighs the potential constraints. I think as PROs and the ways of assessing them continue to develop, that will become a bigger issue. The question will be, okay, you can do this, but what is the value added by doing this? That added value could be demonstrated in terms of better clinical outcomes, reduced costs, reduced hospitalizations, better treatment adherence, and so on.

How do you see the use of patient-reported outcomes in MS care evolving over time?

BRANT OLIVER, PhD: I tend to be optimistic regarding PROs. I think they will become part of the new reality, especially in LHS-oriented models of care. As mentioned, LHSs use feed forward data to predict the needs of people or optimize shared decision-making. I think we're going to see more shared decision-making rather than less over time in complex chronic illnesses care.

In environments where there's an increasing focus on value for high-cost, such as complex chronic conditions like MS and inflammatory bowel disease, systems will have to justify the high cost of treatment. PROs will be a critical piece in making that value assessment, especially since that value assessment is coming from the voice of patients rather than only from clinicians or other stakeholders. Arguably, patients may be able to contribute the most to making the value proposition because it is their outcomes and their experiences that matter to payers. Because experience matters (and not just outcomes), I think we'll see more PREMs used over time, including in MS.

I also think over time we'll see studies working to optimize PROs in the clinical environment and for improvement and research. An early example of that is the MS Continuous Quality Improvement (MS-CQI) Collaborative. It is a prospective randomized multicenter study using patient-reported and clinical data in a LHS approach to study population health outcomes and the effect of quality improvement interventions on those outcomes. It's also optimizing how these PRO measures are actually used at the point of care. Studies like MS-CQI will help to better articulate how, when, and for what purpose PROs should best be used and also when they should be avoided.

I think over time the predictive analytics component of PROs will be emphasized. There is a big push in the MS field in developing biomarkers to help predict disease progression over time. From the predictive analytics or machine learning perspective, imagine a situation where PROs could be used to predict a person's trajectory over time: if they were more likely to be lost to follow-up, to be hospitalized, or to have a relapse in the next year or 2. Reliable PROs generating population health data  at scale can inform the development of risk and outcome predictive models.  

Dr. Oliver discloses that he has received research grant support (MS-CQI research study mentioned in interview). He is the principal investigator and developer of the MS-CQI study, which is grant funded by Biogen under a Sponsored Research Agreement.

Brant Oliver, PhD, MS, MPH, APRN-BC, is a health care improvement and implementation scientist, educator, and board-certified family and psychiatric nurse practitioner (FNP-BC, PMHNP-BC). Dr. Oliver's work focuses on applied health care improvement science research, with a focus on "3C" (complex, costly, and chronic) conditions including MS, IBD, CF, RA, and others; coproduction; learning health systems; and shared decision making. He is Associate Professor at the Geisel School of Medicine at Dartmouth and also has been in clinical practice since 2003, working primarily as a certified MS specialist (MSCN) and a MS neurobehavioral nurse practitioner.  

Which patient-reported outcomes (PROs) are commonly assessed in the care of patients with multiple sclerosis (MS)?

BRANT OLIVER, PhD: The current reality is that PROs are not being used routinely in MS clinical care in most settings. They are most commonly being used in research settings, either as part of clinical trials of new treatments, or in epidemiologic studies looking at the prevalence, incidence, and severity of certain symptoms or functional impairments in MS at the population level. A good example is the NARCOMS registry, which has been used to conduct  high-quality epidemiologic studies of MS-related symptoms using self-report questionnaires.

We are starting to see some use of MS PROs in select clinical settings. Oftentimes these are measures of highly prevalent comorbid conditions that have an impact on quality of life, treatment adherence (depression severity and anxiety), and self-efficacy, which is a measure of perceived coping ability related to self-management of a chronic illness. Also, measures of patient experience are being employed in hospital-based clinics, such as the CG-CAHPS satisfaction measures.

The PROMIS (Patient-Reported Outcomes Measurement Information System) battery is a promising set of PRO measures that are being utilized across a number of conditions and that contain some MS-specific measures, such as the Fatigue MS measure. Fatigue is the most common and disabling symptom in MS, so having a good measure of fatigue is of critical importance. Having a sense of a patient’s experience with fatigue over time can also be very helpful from a clinical perspective. The PROMIS measure performs much better than its predecessor, the Modified Fatigue Impact Scale (MFIS). Another strength of the PROMIS measures is that they tend to do well correlating with other conditions. In certain research and improvement settings, PROMIS can help us understand the burden a particular disease or population places on total health system resources. For example, is fatigue burden in MS similar in severity to that in another 3C condition, such as inflammatory bowel disease?

There are other PRO measures that have not been used in MS but which I think we will see used in the future. One of these is called Collaborate, which falls into the category of patient-reported experience measures (PREMs). Collaborate measures the degree of shared decision-making that occurs in a clinical encounter, which becomes especially important as the complexity of disease-modifying treatment decisions increases as more disease-modifying therapies are introduced, each with their own profile of risks and benefits. I anticipate that the ability of clinics to facilitate effective shared decision-making will be of increasing interest to clinicians, patients, and also payers in the future.

What are some of the potential benefits of using PRO measures in terms of clinician/patient communication and clinical decision-making?

BRANT OLIVER, PhD: I think the most important benefit of measuring PROs is that it can make care more patient-centered. The big push for PROs in the first place was to incorporate more of the patient’s voice into their own care. Standard clinical measures, such as magnetic resonance imaging (MRI) or relapse rates, can be very precise and provide a good clinical picture of how the disease is behaving. But if we rely solely on that kind of information, we can lose sight of the person who is experiencing the disease.

PROs, be they just regular PROs (instruments that gather qualitative and/or quantitative patient-reported information) or PROMs (validated and standardized PRO measures) or PREMs (standardized and validated patient-reported experience measures), all aim to improve the ability to get a better story of the person who's experiencing the illness and how that condition affects them. We can also gain insight on what's most important to them regarding how their illness is managed, and what their experience of care is.

Sometimes the PRO picture and the clinical picture don't necessarily align. I'll tell a story about one a person, who's given me permission to share the story. She is an established professional, and her PRO measures concerning her quality of life, support from her workplace environment, and her ability to function in society are very high. She's very high functioning according to the PRO picture.  However,  her clinical measures suggest that she is significantly impaired. Her MRI burden is quite high, and her disability due to the MS, her EDSS (Expanded Disability Status Scale), is also quite high. So there are 2 very different stories provided by 2 different sets of data. The inclusion of PROs data, in connection with clinical data, can provide a more holistic view of this person, who is functioning well despite significant disease burden.

As a clinician working with patients with MS, this gives me much more to work with in trying to help people, not only treating the disease, but also trying to see where the person is most in need of help. A person could be very well controlled on MRI in terms of relapse rate, but have fatigue severity that is through the roof. If I weren't paying closer attention to that with a validated scale that measures fatigue severity over time, like the PROMIS Fatigue MS, I may not have a sense of how well treatment is helping that person's fatigue longitudinally, beyond what I can glean from the history and clinical examination.

PROs can also be helpful in terms of conditions that are harder to quantify. Depression is a significant cause of disability and a significant factor contributing to poor treatment adherence in MS. Also, the suicide rate in persons with MS is much higher than that in the general population. But there is no blood test for depression severity, and oftentimes a patient’s report on exam can be incomplete or misleading. Accompanying the mental status exam and the clinical evaluation with a validated depression severity measure (such as the PHQ9 [Patient Health Questionnaire-9], CES-D [Center for Epidemiologic Studies Depression Scale], or others) can help to determine whether treatments are having an initial effect, and this can also help with self-monitoring and treatment adherence.  

That brings us to the second area where PROs show real promise in MS care: the learning health system (LHS) approach, which uses feed forward information to either predict the needs of people before they come to the office or optimize decision-making at the point of care (as discussed in our review article published in JCOM).¹

PROs can play a significant role in the LHS approach in 2 ways. For example, if I have a good sense before a visit that the person has stable symptoms but is having a lot of trouble coping with MS, that may change how I allocate resources and focus the time at the visit to target the primary concern of the person before the visit even occurs. Over time I'd be able to monitor if those coping scores increase in response to the work we’re doing with the person.

The second part of this approach is a feedback mechanism. These measures can be aggregated at the population level and fed back to clinical MS centers to help clinicians who are trying to improve overall population health outcomes of people with MS to see how well they're doing on things like fatigue management, depression management, coping ability, and pain control, which can't be tested for with biologic methods. So in addition to looking at the MRI scan trends across the population and relapse rate annualized for the population over time, I'd also be able to see fatigue severity and depression severity at a clinic population level and assess the change in these severity levels over time, which I could then use to inform efforts to change how my system (clinic) provides MS care.

This capability of PROs could be of significant interest to payers, especially those who are looking to optimize the value of care that is being provided, given the high cost of MS care. MS treatments are very expensive, and MS care is multidisciplinary and requires a lot of resources. Payers, I think, will have an increasing interest in assessing the value of high-cost care. PROs could help to demonstrate that value, especially if they can help quantify that outcomes can be improved over time at the population level.

The third area where PROs are beneficial is population health research, especially in terms of the major improvement movements going on in the country, such as those advocated for by the Institute for Healthcare Improvement via the Triple Aim: improve population health outcomes, improve the experience of care, and minimize per capita cost. PROs can really help with the first 2 of those Triple Aim categories.

What are some of the factors that limit the use of PRO measures in MS research and clinical practice?

BRANT OLIVER, PhD: In our JCOM paper,¹ we outlined major barriers or constraints or challenges to implementing PRO measures. One is time and technology in clinical care. It's busy. It's fast. A PRO measure requires patients to complete a questionnaire. And to do that, you need some time and space during the clinical visit, or before the visit, to collect this data. In the absence of appropriate technology, this is done using paper-based methods, which can be challenging. Technology can help. Examples include smart phone app-based collection systems, tablet PCs, or an online mechanism. But there are barriers to technology, too. Is the technology good enough? Is the interface with the people using it working well? Do you have an equal amount of access to and understanding of the technology from the people across your population? Is it only being used by a certain subset that is wealthier and more educated, or maybe who has English as a first language? Such constraints can be overcome, but they’re present in any situation where you are gathering PRO data.

Software constraints also extend to the electronic health record (EHR) capability of the clinics. If you can collect PRO data, does the EHR have the capability to present that data in a useful way during a 20- or 30-minute clinical visit? In other words, does it improve the quality of the visit, or does it generate just one more distraction during the visit? Some approaches, such as feed forward dashboards, provide easy visual displays that can quickly and easily add information at the point of care and can get around this limitation. However, a lot of MS care centers in private practice settings may not have the informatics capability of a large academic center.

 Academic centers often have more EHR capability, but can also  move much slower in implementation than more nimble private practice or community clinics. With many competing demands, it can sometimes take months to build one of these surveys into an EHR, for a task that takes just a day or so. But because other departments are in the queue for these changes, implementation often takes longer than we would intuitively think.

A second barrier is the burden on the individuals themselves. As much as we feel that PROs can make a difference, and the growing literature suggests that they really can, this is counterbalanced with the burden they may place on the patient. For example, a person may arrive at a clinic visit already with a lot on their mind, and then they get a questionnaire to complete in the waiting room before their visit (or perhaps they get asked to do it at home before the visit). The patient, rather than perceiving this as beneficial, may instead perceive it as an extra task or stressor. Explaining the purpose of the PRO measures, encouraging their use, and then actually using the results meaningfully during the visit can substantially improve their perceived value.

It’s important to limit the total amount of PROs used. In research, as well as in clinical settings, too many measures can lead to too little data. It's similar to an overly complex treatment plan: the chance that a person will adhere to all of it decreases with each level of complexity added. This can lead to decreased engagement by patients, and gradually they'll move away from participating in the PROs in general. Research and clinical efforts around PROs strive to get to a parsimonious set of critical measures, which will minimize the burden, but maximize the potential benefit.

 A third challenge is interpretability. This gets into the psychometric properties of the PRO measures and setting appropriate clinical thresholds for what constitutes a “positive” or “actionable” result. What is a clinically significant level of fatigue severity on the PROMIS MS Fatigue? We know that the mean range of that instrument is somewhere between 50 and 60. Does that mean that scores above 60 suggest higher than average fatigue levels, or is it more complicated than that? In many cases, the instruments don't have extensive population level research for the populations in which they are used. Setting clinical thresholds can be difficult, and I suspect that this will be a major area of research in the coming years.

Another example is setting appropriate depression thresholds. We know that on the CES-D, for example, the positive threshold for active depression in a patient with MS may be different from that in a patient without MS, because fatigue is a contributing factor to the neurovegetative symptoms that are scored on the CES-D.

So even if we can incorporate PROs into general practice and minimize burden, we also have to pay attention to factors that limit their interpretability and employ them in a way whereby they provide clinically meaningful results that can help inform care. The good news is,  for many PROs, even with these limitations, this can be done.

Following directly from this is error risk. Many PRO measures were designed for large-sample epidemiologic research, not for a smaller sample clinical practice, which can lead to a higher error risk, especially when following single individuals over time. Adjustments in how these scales are interpreted are required in many cases.

The limitations of many of the respondents completing questionnaires needs to be taken into account. Fatigue and cognitive impairment are very common in MS. Respondents may be selecting answers that are not entirely accurate if they're getting fatigued while doing the surveys, or if they have a comprehension deficit or a short-term memory deficit.

            A final challenge is demonstrating, just like any treatment or assessment approach, that the benefit outweighs the burden. PRO measures that are fairly reliable, validated, and quick and easy to complete suddenly become quite valuable because their benefit far outweighs the potential constraints. I think as PROs and the ways of assessing them continue to develop, that will become a bigger issue. The question will be, okay, you can do this, but what is the value added by doing this? That added value could be demonstrated in terms of better clinical outcomes, reduced costs, reduced hospitalizations, better treatment adherence, and so on.

How do you see the use of patient-reported outcomes in MS care evolving over time?

BRANT OLIVER, PhD: I tend to be optimistic regarding PROs. I think they will become part of the new reality, especially in LHS-oriented models of care. As mentioned, LHSs use feed forward data to predict the needs of people or optimize shared decision-making. I think we're going to see more shared decision-making rather than less over time in complex chronic illnesses care.

In environments where there's an increasing focus on value for high-cost, such as complex chronic conditions like MS and inflammatory bowel disease, systems will have to justify the high cost of treatment. PROs will be a critical piece in making that value assessment, especially since that value assessment is coming from the voice of patients rather than only from clinicians or other stakeholders. Arguably, patients may be able to contribute the most to making the value proposition because it is their outcomes and their experiences that matter to payers. Because experience matters (and not just outcomes), I think we'll see more PREMs used over time, including in MS.

I also think over time we'll see studies working to optimize PROs in the clinical environment and for improvement and research. An early example of that is the MS Continuous Quality Improvement (MS-CQI) Collaborative. It is a prospective randomized multicenter study using patient-reported and clinical data in a LHS approach to study population health outcomes and the effect of quality improvement interventions on those outcomes. It's also optimizing how these PRO measures are actually used at the point of care. Studies like MS-CQI will help to better articulate how, when, and for what purpose PROs should best be used and also when they should be avoided.

I think over time the predictive analytics component of PROs will be emphasized. There is a big push in the MS field in developing biomarkers to help predict disease progression over time. From the predictive analytics or machine learning perspective, imagine a situation where PROs could be used to predict a person's trajectory over time: if they were more likely to be lost to follow-up, to be hospitalized, or to have a relapse in the next year or 2. Reliable PROs generating population health data  at scale can inform the development of risk and outcome predictive models.  

Dr. Oliver discloses that he has received research grant support (MS-CQI research study mentioned in interview). He is the principal investigator and developer of the MS-CQI study, which is grant funded by Biogen under a Sponsored Research Agreement.

Chronic conditions such as lung disease, diabetes, and heart disease frequently receive attention for increasing the risk of complications for people who contract the coronavirus. Meanwhile, many members of the epilepsy community continue to wonder how the virus affects them. To address these concerns, the Epilepsy Foundation has released information that answers many common questions that people with epilepsy have about how COVID-19 can impact their health.

Perhaps the most pressing of these questions is: Does epilepsy increase the risk or severity of the coronavirus? According to the Epilepsy Foundation’s website, having epilepsy poses no additional risk for contracting COVID-19 or worsening the severity of the virus.

“The most common thing we’re hearing from patients in my practice is their proactive concern for being at increased risk for getting the coronavirus,” confirmed Selim Benbadis, MD, division director, epilepsy, EEG, and sleep medicine at the University of South Florida in Tampa. “Epilepsy patients are not at increased risk for complications from the coronavirus because epilepsy does not affect the immune system.”

In other words, people who have epilepsy face the same health challenges as people who do not have the condition and are otherwise healthy. For this reason, people who have epilepsy should exercise the same habits and preventative measures that healthy people would typically take, such as social distancing; avoiding contact with sick people; washing hands regularly; disinfecting surfaces regularly; and avoiding touching hands, eyes, nose and mouth.

However, as Dr. Benbadis explained, the high fever associated with coronavirus can trigger seizures. The increased risk is another reason people who have epilepsy should do their best to avoid getting sick.
 

Seizure medications do not increase COVID-19 risk but other conditions can

Similarly, epilepsy medications do not increase the risk of contracting the disease.

“The medications patients take to treat their epilepsy do not affect their immune system,” said Andrew Wilner, MD, associate professor of neurology at the University of Tennessee Health Science Center, Memphis. There are a few exceptions – such as adrenocorticotropic hormone and everolimus – but doctors rarely use these drugs to treat epilepsy.

However, there are some situations and conditions that may pose a risk for people who contact the coronavirus. For instance, people who have problems swallowing their food and tend to suck food down their windpipes are more likely to develop pneumonia. Also, much like the general population, having diabetes, heart disease, or lung problems increase the chances of developing complications from the virus.
 

The best ways to avoid additional risks in epilepsy

Because of the pandemic, people who have epilepsy may have found that many of their doctors’ appointments have been canceled. Many clinics and medical practices have done this in order minimize exposing people who have acute illnesses to the virus. By focusing more on patients with acute conditions, doctors and nurses can better tend to patients with acute problems. As a result, practices have shifted to providing patient care using telemedicine as much as possible.

“Telemedicine services have surged, and I’ve been saying for years that telemedicine was going to grow,” Dr. Benbadis said. “It’s more convenient, and I believe that we’re going to see increased use of telemedicine long after the coronavirus pandemic is over.”

Aside from communicating with their doctors, the Epilepsy Foundation and Dr. Wilner stress that the best way for people who have epilepsy to stay healthy is by taking their medications on a regular basis exactly as prescribed.

“Taking mediation correctly and regularly is the best strategy for epilepsy patients to avoid unnecessary hospitalizations,” Dr. Wilner said. “If they have breakthrough seizures and get sent to the emergency room, then they risk being exposed to the virus in the ER.”

Also, because ERs are more crowded than usual, the Epilepsy Foundation encourages people who suspect they have the coronavirus to call their doctor’s office first. The goal is to try to make sure that people who have severe or life-threatening symptoms have access to treatment in the ER.

As with the general population, the first thing that epilepsy patients who suspect they have the coronavirus should do is call his or her doctor’s office. The health care professional taking the call will ask the patient a series of questions to determine whether the patient has COVID-19 or another condition or needs to seek emergency medical attention.

Fever, cough, and trouble breathing fall among the most commonly reported symptoms of the coronavirus. In many cases, health care providers recommend that people with mild versions of these symptoms stay at home.
 

Helpful tips

The Epilepsy Foundation offers tips on signs to look for when trying to figure out when a seizure requires an ER visit. These are:

• Seizures in which awareness is lost for more than 5 minutes and no reversal medications are available.
• Seizures with an unusual pattern or duration.
• Seizures that cannot be treated safely at home or are not responding to rescue medication even after the medication has had enough time to work.
• Seizures that occur after a severe blow to the head.

Additionally, while COVID-19 can cause death and sudden death in patients, the virus does not cause sudden unexpected death in epilepsy (SUDEP). Because SUDEP is extremely rare, Dr. Benbadis said that there is no information to suggest that contracting the coronavirus will increase the risk,

Finally, no shortages of seizures medications have been reported as a result of COVID-19. However, there were shortages of generic levetiracetam immediate-release and levetiracetam extended-release medications prior to and during COVID-19. Experts expect the shortage to continue.

Overall, people who have epilepsy should be able to stay healthy – provided they exercise healthy and preventative habits.

“The majority of epilepsy patients should be reassured that if they continue their usual care, take their meds as directed, get adequate sleep, nutritious diet, they’re not at any increased risk compared to the general population,” said Dr. Wilner.

Dr. Benbadis reported the following disclosures: consultant for Bioserenity (DigiTrace), Brain Sentinel, Cavion, Ceribell, Eisai, Greenwich, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion; speakers bureau for Eisai, Greenwich, LivaNova, Sunovion; Florida Medical Director of Stratus/Alliance; Member: Epilepsy Study Consortium; grant support from Cavion, LivaNova, Greenwich, SK biopharmaceuticals, Sunovion, Takeda, UCB, Xenon; royalties as an author or editor for Emedicine-Medscape-WebMD, UpToDate; editorial board for the Epilepsy.com (Epilepsy Foundation) controversy section, Emedicine-Medscape-WebMD, Epileptic Disorders, Epilepsy and Behavior, and Expert Review of Neurotherapeutics. Dr. Wilner reports Medical Advisory Board of Accordant Health Services, Greensboro, S.C., and book royalties: “The Locum Life: A Physician’s Guide to Locum Tenens,” Lulu Press.
 

Chronic conditions such as lung disease, diabetes, and heart disease frequently receive attention for increasing the risk of complications for people who contract the coronavirus. Meanwhile, many members of the epilepsy community continue to wonder how the virus affects them. To address these concerns, the Epilepsy Foundation has released information that answers many common questions that people with epilepsy have about how COVID-19 can impact their health.

Perhaps the most pressing of these questions is: Does epilepsy increase the risk or severity of the coronavirus? According to the Epilepsy Foundation’s website, having epilepsy poses no additional risk for contracting COVID-19 or worsening the severity of the virus.

“The most common thing we’re hearing from patients in my practice is their proactive concern for being at increased risk for getting the coronavirus,” confirmed Selim Benbadis, MD, division director, epilepsy, EEG, and sleep medicine at the University of South Florida in Tampa. “Epilepsy patients are not at increased risk for complications from the coronavirus because epilepsy does not affect the immune system.”

In other words, people who have epilepsy face the same health challenges as people who do not have the condition and are otherwise healthy. For this reason, people who have epilepsy should exercise the same habits and preventative measures that healthy people would typically take, such as social distancing; avoiding contact with sick people; washing hands regularly; disinfecting surfaces regularly; and avoiding touching hands, eyes, nose and mouth.

However, as Dr. Benbadis explained, the high fever associated with coronavirus can trigger seizures. The increased risk is another reason people who have epilepsy should do their best to avoid getting sick.
 

Seizure medications do not increase COVID-19 risk but other conditions can

Similarly, epilepsy medications do not increase the risk of contracting the disease.

“The medications patients take to treat their epilepsy do not affect their immune system,” said Andrew Wilner, MD, associate professor of neurology at the University of Tennessee Health Science Center, Memphis. There are a few exceptions – such as adrenocorticotropic hormone and everolimus – but doctors rarely use these drugs to treat epilepsy.

However, there are some situations and conditions that may pose a risk for people who contact the coronavirus. For instance, people who have problems swallowing their food and tend to suck food down their windpipes are more likely to develop pneumonia. Also, much like the general population, having diabetes, heart disease, or lung problems increase the chances of developing complications from the virus.
 

The best ways to avoid additional risks in epilepsy

Because of the pandemic, people who have epilepsy may have found that many of their doctors’ appointments have been canceled. Many clinics and medical practices have done this in order minimize exposing people who have acute illnesses to the virus. By focusing more on patients with acute conditions, doctors and nurses can better tend to patients with acute problems. As a result, practices have shifted to providing patient care using telemedicine as much as possible.

“Telemedicine services have surged, and I’ve been saying for years that telemedicine was going to grow,” Dr. Benbadis said. “It’s more convenient, and I believe that we’re going to see increased use of telemedicine long after the coronavirus pandemic is over.”

Aside from communicating with their doctors, the Epilepsy Foundation and Dr. Wilner stress that the best way for people who have epilepsy to stay healthy is by taking their medications on a regular basis exactly as prescribed.

“Taking mediation correctly and regularly is the best strategy for epilepsy patients to avoid unnecessary hospitalizations,” Dr. Wilner said. “If they have breakthrough seizures and get sent to the emergency room, then they risk being exposed to the virus in the ER.”

Also, because ERs are more crowded than usual, the Epilepsy Foundation encourages people who suspect they have the coronavirus to call their doctor’s office first. The goal is to try to make sure that people who have severe or life-threatening symptoms have access to treatment in the ER.

As with the general population, the first thing that epilepsy patients who suspect they have the coronavirus should do is call his or her doctor’s office. The health care professional taking the call will ask the patient a series of questions to determine whether the patient has COVID-19 or another condition or needs to seek emergency medical attention.

Fever, cough, and trouble breathing fall among the most commonly reported symptoms of the coronavirus. In many cases, health care providers recommend that people with mild versions of these symptoms stay at home.
 

Helpful tips

The Epilepsy Foundation offers tips on signs to look for when trying to figure out when a seizure requires an ER visit. These are:

• Seizures in which awareness is lost for more than 5 minutes and no reversal medications are available.
• Seizures with an unusual pattern or duration.
• Seizures that cannot be treated safely at home or are not responding to rescue medication even after the medication has had enough time to work.
• Seizures that occur after a severe blow to the head.

Additionally, while COVID-19 can cause death and sudden death in patients, the virus does not cause sudden unexpected death in epilepsy (SUDEP). Because SUDEP is extremely rare, Dr. Benbadis said that there is no information to suggest that contracting the coronavirus will increase the risk,

Finally, no shortages of seizures medications have been reported as a result of COVID-19. However, there were shortages of generic levetiracetam immediate-release and levetiracetam extended-release medications prior to and during COVID-19. Experts expect the shortage to continue.

Overall, people who have epilepsy should be able to stay healthy – provided they exercise healthy and preventative habits.

“The majority of epilepsy patients should be reassured that if they continue their usual care, take their meds as directed, get adequate sleep, nutritious diet, they’re not at any increased risk compared to the general population,” said Dr. Wilner.

Dr. Benbadis reported the following disclosures: consultant for Bioserenity (DigiTrace), Brain Sentinel, Cavion, Ceribell, Eisai, Greenwich, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion; speakers bureau for Eisai, Greenwich, LivaNova, Sunovion; Florida Medical Director of Stratus/Alliance; Member: Epilepsy Study Consortium; grant support from Cavion, LivaNova, Greenwich, SK biopharmaceuticals, Sunovion, Takeda, UCB, Xenon; royalties as an author or editor for Emedicine-Medscape-WebMD, UpToDate; editorial board for the Epilepsy.com (Epilepsy Foundation) controversy section, Emedicine-Medscape-WebMD, Epileptic Disorders, Epilepsy and Behavior, and Expert Review of Neurotherapeutics. Dr. Wilner reports Medical Advisory Board of Accordant Health Services, Greensboro, S.C., and book royalties: “The Locum Life: A Physician’s Guide to Locum Tenens,” Lulu Press.
 

Chronic conditions such as lung disease, diabetes, and heart disease frequently receive attention for increasing the risk of complications for people who contract the coronavirus. Meanwhile, many members of the epilepsy community continue to wonder how the virus affects them. To address these concerns, the Epilepsy Foundation has released information that answers many common questions that people with epilepsy have about how COVID-19 can impact their health.

Perhaps the most pressing of these questions is: Does epilepsy increase the risk or severity of the coronavirus? According to the Epilepsy Foundation’s website, having epilepsy poses no additional risk for contracting COVID-19 or worsening the severity of the virus.

“The most common thing we’re hearing from patients in my practice is their proactive concern for being at increased risk for getting the coronavirus,” confirmed Selim Benbadis, MD, division director, epilepsy, EEG, and sleep medicine at the University of South Florida in Tampa. “Epilepsy patients are not at increased risk for complications from the coronavirus because epilepsy does not affect the immune system.”

In other words, people who have epilepsy face the same health challenges as people who do not have the condition and are otherwise healthy. For this reason, people who have epilepsy should exercise the same habits and preventative measures that healthy people would typically take, such as social distancing; avoiding contact with sick people; washing hands regularly; disinfecting surfaces regularly; and avoiding touching hands, eyes, nose and mouth.

However, as Dr. Benbadis explained, the high fever associated with coronavirus can trigger seizures. The increased risk is another reason people who have epilepsy should do their best to avoid getting sick.
 

Seizure medications do not increase COVID-19 risk but other conditions can

Similarly, epilepsy medications do not increase the risk of contracting the disease.

“The medications patients take to treat their epilepsy do not affect their immune system,” said Andrew Wilner, MD, associate professor of neurology at the University of Tennessee Health Science Center, Memphis. There are a few exceptions – such as adrenocorticotropic hormone and everolimus – but doctors rarely use these drugs to treat epilepsy.

However, there are some situations and conditions that may pose a risk for people who contact the coronavirus. For instance, people who have problems swallowing their food and tend to suck food down their windpipes are more likely to develop pneumonia. Also, much like the general population, having diabetes, heart disease, or lung problems increase the chances of developing complications from the virus.
 

The best ways to avoid additional risks in epilepsy

Because of the pandemic, people who have epilepsy may have found that many of their doctors’ appointments have been canceled. Many clinics and medical practices have done this in order minimize exposing people who have acute illnesses to the virus. By focusing more on patients with acute conditions, doctors and nurses can better tend to patients with acute problems. As a result, practices have shifted to providing patient care using telemedicine as much as possible.

“Telemedicine services have surged, and I’ve been saying for years that telemedicine was going to grow,” Dr. Benbadis said. “It’s more convenient, and I believe that we’re going to see increased use of telemedicine long after the coronavirus pandemic is over.”

Aside from communicating with their doctors, the Epilepsy Foundation and Dr. Wilner stress that the best way for people who have epilepsy to stay healthy is by taking their medications on a regular basis exactly as prescribed.

“Taking mediation correctly and regularly is the best strategy for epilepsy patients to avoid unnecessary hospitalizations,” Dr. Wilner said. “If they have breakthrough seizures and get sent to the emergency room, then they risk being exposed to the virus in the ER.”

Also, because ERs are more crowded than usual, the Epilepsy Foundation encourages people who suspect they have the coronavirus to call their doctor’s office first. The goal is to try to make sure that people who have severe or life-threatening symptoms have access to treatment in the ER.

As with the general population, the first thing that epilepsy patients who suspect they have the coronavirus should do is call his or her doctor’s office. The health care professional taking the call will ask the patient a series of questions to determine whether the patient has COVID-19 or another condition or needs to seek emergency medical attention.

Fever, cough, and trouble breathing fall among the most commonly reported symptoms of the coronavirus. In many cases, health care providers recommend that people with mild versions of these symptoms stay at home.
 

Helpful tips

The Epilepsy Foundation offers tips on signs to look for when trying to figure out when a seizure requires an ER visit. These are:

• Seizures in which awareness is lost for more than 5 minutes and no reversal medications are available.
• Seizures with an unusual pattern or duration.
• Seizures that cannot be treated safely at home or are not responding to rescue medication even after the medication has had enough time to work.
• Seizures that occur after a severe blow to the head.

Additionally, while COVID-19 can cause death and sudden death in patients, the virus does not cause sudden unexpected death in epilepsy (SUDEP). Because SUDEP is extremely rare, Dr. Benbadis said that there is no information to suggest that contracting the coronavirus will increase the risk,

Finally, no shortages of seizures medications have been reported as a result of COVID-19. However, there were shortages of generic levetiracetam immediate-release and levetiracetam extended-release medications prior to and during COVID-19. Experts expect the shortage to continue.

Overall, people who have epilepsy should be able to stay healthy – provided they exercise healthy and preventative habits.

“The majority of epilepsy patients should be reassured that if they continue their usual care, take their meds as directed, get adequate sleep, nutritious diet, they’re not at any increased risk compared to the general population,” said Dr. Wilner.

Dr. Benbadis reported the following disclosures: consultant for Bioserenity (DigiTrace), Brain Sentinel, Cavion, Ceribell, Eisai, Greenwich, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion; speakers bureau for Eisai, Greenwich, LivaNova, Sunovion; Florida Medical Director of Stratus/Alliance; Member: Epilepsy Study Consortium; grant support from Cavion, LivaNova, Greenwich, SK biopharmaceuticals, Sunovion, Takeda, UCB, Xenon; royalties as an author or editor for Emedicine-Medscape-WebMD, UpToDate; editorial board for the Epilepsy.com (Epilepsy Foundation) controversy section, Emedicine-Medscape-WebMD, Epileptic Disorders, Epilepsy and Behavior, and Expert Review of Neurotherapeutics. Dr. Wilner reports Medical Advisory Board of Accordant Health Services, Greensboro, S.C., and book royalties: “The Locum Life: A Physician’s Guide to Locum Tenens,” Lulu Press.
 

Children with refractory epilepsy who took pharmaceutical cannabidiol (CBD) had higher serum CBD levels and better seizure control than those who took artisanal CBD, but they had more adverse side effects, preliminary results of a small study indicate.

Given the widespread use of artisanal CBD products, Nathan T. Cohen, MD, pediatric epilepsy fellow, Children’s National Hospital, Washington, DC, and his colleagues wanted to know how these products differ from pharmaceutical grade CBD with respect to seizure control.

“One of the challenges or questions we have is whether there is any information that would guide us and suggest patients transition from artisanal to pharmaceutical grade CBD,” Dr. Cohen, who is lead author of the study, told Medscape Medical News.

The findings were released February 27 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage. The study received no outside funding.

In addition to helping relieve anxiety and stress, CBD, one of many constituents of Cannabis sativa, has antiseizure properties. The US Food and Drug Administration (FDA) has approved a pharmaceutical CBD (Epidiolex, GW Pharmaceuticals) for the management of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome.

This purified oral CBD prescription product does not contain tetrahydrocannabinol (THC), the component of marijuana that produces a “high.”
 

Popular products

Artisanal CBD, which has been around since the late 1970s, is manufactured using variable amounts of CBD and THC. Artisanal products, which typically come in the form of oils that are swallowed, are available in dispensaries and elsewhere, depending on the legal status in individual states.

These artisanal formulations are popular among patients with epilepsy and their families. On the basis of the advertising he sees, Dr. Cohen estimates there are at least 100 artisanal CBD products, but he was quick to stress he’s not an expert on artisanal CBD.

He noted that some families are “searching for an alternative treatment” to help control their child’s seizures, and if the seizure syndrome isn’t LGS or Dravet, “then technically, they don’t qualify for prescription-strength CBD,” said Dr. Cohen.

The current study was a retrospective chart review and included patients with epilepsy who underwent treatment with artisanal or pharmaceutical CBD for whom serum CBD levels were available.

In addition to CBD levels, the researchers had information on patients’ date of birth, gender, epilepsy diagnosis, artisanal or pharmaceutical CBD dose, seizure history, and side effects, among other things.

The analysis included 31 patients (48% female; mean age, about 10 years). Of these, 32% had LGS, 6% had Dravet, and the rest had other epilepsy syndromes.

Of the total, 22 patients participated in a pharmaceutical CBD expanded-access program. The remaining nine patients received artisanal CBD.

The mean serum CBD level was 30.1 ng/mL in the artisanal group and 124 ng/mL in the pharmaceutical group.

Dr. Cohen noted that artisanal products contain lower amounts of CBD because they’re not purified, and they may contain other compounds derived from marijuana.

At the last follow-up, which was a median of 11.8 months, patients who took artisanal CBD had a 70% increase in overall seizures. Dr. Cohen pointed out that some of the hundreds of compounds in marijuana could be “pro-convulsant.”
 

Some seizure free

The prescription CBD group experienced a 39% reduction in seizures. “Some of these kids had up to hundreds of seizures a day and went down to tens, and some kids became seizure free,” said Dr. Cohen.

Because the study was “looking back in time,” the investigators couldn’t determine whether age, type of epilepsy, or other factors affected seizure control in the two groups, said Dr. Cohen. “One of the limitations of a retrospective study is that we’re not able to control for those factors,” he said.

Eleven patients—all in the prescription CBD group—reported adverse effects, including somnolence, emesis, diarrhea, and diminished appetite; six discontinued CBD because of side effects.

Dr. Cohen said he’s not aware of any study that has compared artisanal products “head to head” with pharmaceutical grade CBD. “The whole point of this study was to ask the question, Is there a difference between the groups?, and these new data would suggest that there may be.”

The results appear to support giving encouragement to patients to transition from artisanal to pharmaceutical CBD if appropriate. “Anytime you’re giving your child a medication that has not been produced under the stringent guidelines that all pharmaceutical FDA-approved medications undergo, you don’t know exactly what’s in the product, and not knowing is a potential issue,” said Dr. Cohen.

The findings need to be studied in a more controlled setting “to make sure they’re valid,” said Dr. Cohen. Because this is “a very hot topic,” he’s keen to see what further research his colleagues would be interested in pursuing.

Commenting on the research, Joseph Sirven, MD, a neurologist in Scottsdale, Arizona, said this is an important study.

“It highlights one of the most common questions that I receive almost on a daily basis in my neurology practice,” he said.

Most people think that dispensary-based CBD is the same as prescription-based CBD, said Dr. Sirven. “Technically and theoretically, they certainly could be; however, what this study highlights is that in practice, they are not the same.”

He stressed that prescription CBD has to meet certain quality standards. “That means that whatever the ingredient list states about the concentration of CBD in the product has to be within the product, which is why the FDA approved it. It is, in essence, a quality control issue.”

A dispensary-based product does not need to meet such stringent standards and so “is subject to whatever the manufacturer chooses to put in the product,” said Dr. Sirven.

The study received no outside funding. Drs. Cohen and Sirven reported no relevant financial relationships.

This article first appeared on Medscape.com.

Children with refractory epilepsy who took pharmaceutical cannabidiol (CBD) had higher serum CBD levels and better seizure control than those who took artisanal CBD, but they had more adverse side effects, preliminary results of a small study indicate.

Given the widespread use of artisanal CBD products, Nathan T. Cohen, MD, pediatric epilepsy fellow, Children’s National Hospital, Washington, DC, and his colleagues wanted to know how these products differ from pharmaceutical grade CBD with respect to seizure control.

“One of the challenges or questions we have is whether there is any information that would guide us and suggest patients transition from artisanal to pharmaceutical grade CBD,” Dr. Cohen, who is lead author of the study, told Medscape Medical News.

The findings were released February 27 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage. The study received no outside funding.

In addition to helping relieve anxiety and stress, CBD, one of many constituents of Cannabis sativa, has antiseizure properties. The US Food and Drug Administration (FDA) has approved a pharmaceutical CBD (Epidiolex, GW Pharmaceuticals) for the management of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome.

This purified oral CBD prescription product does not contain tetrahydrocannabinol (THC), the component of marijuana that produces a “high.”
 

Popular products

Artisanal CBD, which has been around since the late 1970s, is manufactured using variable amounts of CBD and THC. Artisanal products, which typically come in the form of oils that are swallowed, are available in dispensaries and elsewhere, depending on the legal status in individual states.

These artisanal formulations are popular among patients with epilepsy and their families. On the basis of the advertising he sees, Dr. Cohen estimates there are at least 100 artisanal CBD products, but he was quick to stress he’s not an expert on artisanal CBD.

He noted that some families are “searching for an alternative treatment” to help control their child’s seizures, and if the seizure syndrome isn’t LGS or Dravet, “then technically, they don’t qualify for prescription-strength CBD,” said Dr. Cohen.

The current study was a retrospective chart review and included patients with epilepsy who underwent treatment with artisanal or pharmaceutical CBD for whom serum CBD levels were available.

In addition to CBD levels, the researchers had information on patients’ date of birth, gender, epilepsy diagnosis, artisanal or pharmaceutical CBD dose, seizure history, and side effects, among other things.

The analysis included 31 patients (48% female; mean age, about 10 years). Of these, 32% had LGS, 6% had Dravet, and the rest had other epilepsy syndromes.

Of the total, 22 patients participated in a pharmaceutical CBD expanded-access program. The remaining nine patients received artisanal CBD.

The mean serum CBD level was 30.1 ng/mL in the artisanal group and 124 ng/mL in the pharmaceutical group.

Dr. Cohen noted that artisanal products contain lower amounts of CBD because they’re not purified, and they may contain other compounds derived from marijuana.

At the last follow-up, which was a median of 11.8 months, patients who took artisanal CBD had a 70% increase in overall seizures. Dr. Cohen pointed out that some of the hundreds of compounds in marijuana could be “pro-convulsant.”
 

Some seizure free

The prescription CBD group experienced a 39% reduction in seizures. “Some of these kids had up to hundreds of seizures a day and went down to tens, and some kids became seizure free,” said Dr. Cohen.

Because the study was “looking back in time,” the investigators couldn’t determine whether age, type of epilepsy, or other factors affected seizure control in the two groups, said Dr. Cohen. “One of the limitations of a retrospective study is that we’re not able to control for those factors,” he said.

Eleven patients—all in the prescription CBD group—reported adverse effects, including somnolence, emesis, diarrhea, and diminished appetite; six discontinued CBD because of side effects.

Dr. Cohen said he’s not aware of any study that has compared artisanal products “head to head” with pharmaceutical grade CBD. “The whole point of this study was to ask the question, Is there a difference between the groups?, and these new data would suggest that there may be.”

The results appear to support giving encouragement to patients to transition from artisanal to pharmaceutical CBD if appropriate. “Anytime you’re giving your child a medication that has not been produced under the stringent guidelines that all pharmaceutical FDA-approved medications undergo, you don’t know exactly what’s in the product, and not knowing is a potential issue,” said Dr. Cohen.

The findings need to be studied in a more controlled setting “to make sure they’re valid,” said Dr. Cohen. Because this is “a very hot topic,” he’s keen to see what further research his colleagues would be interested in pursuing.

Commenting on the research, Joseph Sirven, MD, a neurologist in Scottsdale, Arizona, said this is an important study.

“It highlights one of the most common questions that I receive almost on a daily basis in my neurology practice,” he said.

Most people think that dispensary-based CBD is the same as prescription-based CBD, said Dr. Sirven. “Technically and theoretically, they certainly could be; however, what this study highlights is that in practice, they are not the same.”

He stressed that prescription CBD has to meet certain quality standards. “That means that whatever the ingredient list states about the concentration of CBD in the product has to be within the product, which is why the FDA approved it. It is, in essence, a quality control issue.”

A dispensary-based product does not need to meet such stringent standards and so “is subject to whatever the manufacturer chooses to put in the product,” said Dr. Sirven.

The study received no outside funding. Drs. Cohen and Sirven reported no relevant financial relationships.

This article first appeared on Medscape.com.

Children with refractory epilepsy who took pharmaceutical cannabidiol (CBD) had higher serum CBD levels and better seizure control than those who took artisanal CBD, but they had more adverse side effects, preliminary results of a small study indicate.

Given the widespread use of artisanal CBD products, Nathan T. Cohen, MD, pediatric epilepsy fellow, Children’s National Hospital, Washington, DC, and his colleagues wanted to know how these products differ from pharmaceutical grade CBD with respect to seizure control.

“One of the challenges or questions we have is whether there is any information that would guide us and suggest patients transition from artisanal to pharmaceutical grade CBD,” Dr. Cohen, who is lead author of the study, told Medscape Medical News.

The findings were released February 27 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage. The study received no outside funding.

In addition to helping relieve anxiety and stress, CBD, one of many constituents of Cannabis sativa, has antiseizure properties. The US Food and Drug Administration (FDA) has approved a pharmaceutical CBD (Epidiolex, GW Pharmaceuticals) for the management of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome.

This purified oral CBD prescription product does not contain tetrahydrocannabinol (THC), the component of marijuana that produces a “high.”
 

Popular products

Artisanal CBD, which has been around since the late 1970s, is manufactured using variable amounts of CBD and THC. Artisanal products, which typically come in the form of oils that are swallowed, are available in dispensaries and elsewhere, depending on the legal status in individual states.

These artisanal formulations are popular among patients with epilepsy and their families. On the basis of the advertising he sees, Dr. Cohen estimates there are at least 100 artisanal CBD products, but he was quick to stress he’s not an expert on artisanal CBD.

He noted that some families are “searching for an alternative treatment” to help control their child’s seizures, and if the seizure syndrome isn’t LGS or Dravet, “then technically, they don’t qualify for prescription-strength CBD,” said Dr. Cohen.

The current study was a retrospective chart review and included patients with epilepsy who underwent treatment with artisanal or pharmaceutical CBD for whom serum CBD levels were available.

In addition to CBD levels, the researchers had information on patients’ date of birth, gender, epilepsy diagnosis, artisanal or pharmaceutical CBD dose, seizure history, and side effects, among other things.

The analysis included 31 patients (48% female; mean age, about 10 years). Of these, 32% had LGS, 6% had Dravet, and the rest had other epilepsy syndromes.

Of the total, 22 patients participated in a pharmaceutical CBD expanded-access program. The remaining nine patients received artisanal CBD.

The mean serum CBD level was 30.1 ng/mL in the artisanal group and 124 ng/mL in the pharmaceutical group.

Dr. Cohen noted that artisanal products contain lower amounts of CBD because they’re not purified, and they may contain other compounds derived from marijuana.

At the last follow-up, which was a median of 11.8 months, patients who took artisanal CBD had a 70% increase in overall seizures. Dr. Cohen pointed out that some of the hundreds of compounds in marijuana could be “pro-convulsant.”
 

Some seizure free

The prescription CBD group experienced a 39% reduction in seizures. “Some of these kids had up to hundreds of seizures a day and went down to tens, and some kids became seizure free,” said Dr. Cohen.

Because the study was “looking back in time,” the investigators couldn’t determine whether age, type of epilepsy, or other factors affected seizure control in the two groups, said Dr. Cohen. “One of the limitations of a retrospective study is that we’re not able to control for those factors,” he said.

Eleven patients—all in the prescription CBD group—reported adverse effects, including somnolence, emesis, diarrhea, and diminished appetite; six discontinued CBD because of side effects.

Dr. Cohen said he’s not aware of any study that has compared artisanal products “head to head” with pharmaceutical grade CBD. “The whole point of this study was to ask the question, Is there a difference between the groups?, and these new data would suggest that there may be.”

The results appear to support giving encouragement to patients to transition from artisanal to pharmaceutical CBD if appropriate. “Anytime you’re giving your child a medication that has not been produced under the stringent guidelines that all pharmaceutical FDA-approved medications undergo, you don’t know exactly what’s in the product, and not knowing is a potential issue,” said Dr. Cohen.

The findings need to be studied in a more controlled setting “to make sure they’re valid,” said Dr. Cohen. Because this is “a very hot topic,” he’s keen to see what further research his colleagues would be interested in pursuing.

Commenting on the research, Joseph Sirven, MD, a neurologist in Scottsdale, Arizona, said this is an important study.

“It highlights one of the most common questions that I receive almost on a daily basis in my neurology practice,” he said.

Most people think that dispensary-based CBD is the same as prescription-based CBD, said Dr. Sirven. “Technically and theoretically, they certainly could be; however, what this study highlights is that in practice, they are not the same.”

He stressed that prescription CBD has to meet certain quality standards. “That means that whatever the ingredient list states about the concentration of CBD in the product has to be within the product, which is why the FDA approved it. It is, in essence, a quality control issue.”

A dispensary-based product does not need to meet such stringent standards and so “is subject to whatever the manufacturer chooses to put in the product,” said Dr. Sirven.

The study received no outside funding. Drs. Cohen and Sirven reported no relevant financial relationships.

This article first appeared on Medscape.com.

Boxing may help improve common nonmotor symptoms of Parkinson’s disease, new research suggests. In the study, patients with Parkinson’s disease who participated in a noncontact boxing program experienced improvement in nonmotor symptoms such as fatigue, depression, and anxiety, and had significantly better quality of life compared with their counterparts who did not engage in this type of exercise.

“We know we should be prescribing exercise for our Parkinson’s disease patients because more and more research shows it can delay the progression of the disease, but it can be overwhelming to know what type of exercise to prescribe to patients,” study investigator Danielle Larson, MD, a neurologist and movement disorders fellow at Northwestern University, Chicago, Illinois, told Medscape Medical News.

On a daily basis, patients at Dr. Larson’s clinic who have taken Rock Steady Boxing (RSB) classes “really endorse” this exercise, she said.

The findings were released March 4 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
 

Global program

A form of noncontact boxing, RSB was created in 2006 for patients with Parkinson’s disease. A typical 90-minute class starts with stretching and cardiovascular exercises, then foot movements and stepping over obstacles.

“Parkinson’s disease patients are slowed down and have difficulty navigating around obstacles,” Dr. Larson noted.

The class also includes “speed training,” such as fast walking or running. In the boxing part of the class, participants use suspended punching bags.

Dr. Larson said the RSB program caters to all patients with Parkinson’s disease, “even those who need a walker for assistance.” Most RSB sites require a release from a physician to ensure patient safety, she said.

There are now about 43,500 participants at 871 RSB sites around the world.

Adults with Parkinson’s disease who were aware of RSB completed a 20-minute anonymous survey, distributed via email and social media by RSB Inc and the Parkinson Foundation.

Of 2,054 survey respondents, 1,709 were eligible for analysis. Of these, 1,333 were currently participating in RSB, 166 had previously participated, and 210 had never participated in the program.

For all three groups, researchers gathered demographic information, such as age, gender, and income, and asked respondents how long they had the condition, who takes care of their illness, etc.

Current and previous RSB participants were asked about the exercise. For example, they were asked how many classes on average they would take per week and whether specific symptoms had improved or not changed with their participation.

RSB participants had a mean age of 69 years, 59% were male, and 96% were white. Demographics were similar for the other groups, although Dr. Larson noted that the group that had never participated was relatively small.

There was no difference between the groups in terms of years since Parkinson’ disease diagnosis or use of a movement disorders specialist.

Less fatigue

Compared with nonparticipants, a higher percentage of participants were retired (76% vs. 65%, P < .01) and married/had a partner (85% vs. 80%, P = .03).

The symptoms for which participants reported at least a 50% improvement were mostly nonmotor symptoms. For example, participants had improvements in social life (70%), fatigue (63%), fear of falling (62%), depression (60%), and anxiety (59%).

More than 50% of respondents in the previous participant group also reported improvement in these symptoms, “just not to the same degree as the current participants,” Dr. Larson said.

“Those symptoms are difficult to treat in Parkinson’s disease,” she noted. “We really don’t have any good medications for those symptoms; so to report, for example, a 63% improvement in fatigue is pretty substantial.”

The survey included the Parkinson’s Disease Questionnaire–39 (PDQ-39). The questionnaire assesses factors associated with daily living, including relationships and the impact of Parkinson’s disease on functioning and well-being.

Compared with nonparticipants, current participants had better mean scores on the PDQ-39 (25 vs. 32, P < .01), which indicates better quality of life, Dr. Larson said. Previous participants had a higher (or worse) score than current participants, she added.

Largest study to date

Researchers also examined likelihood of exercising even with certain barriers, such as distance to the gym, bad weather, or fatigue using the Self Efficacy for Exercise (SEE) Scale. Current participants had better SEE scores compared with nonparticipants (54 vs. 48, P < .01).

“We can’t prove causality. We can’t say it was the RSB that improved their quality of life or their exercise self-efficacy, but at least there’s a correlation,” Dr. Larson said.

For the SEE, again, the previous participants had lower scores than current participants, she noted.

“An interpretation of this is that individuals who previously participated but stopped did so because they had lower exercise self-efficacy – which is the ability to self-motivate and stick with an exercise – to begin with,” she said.

As for Parkinson’s disease–related motor symptoms, the survey found some improvements. “People did report between 20% and 40% improvement on various motor symptoms,” but not more than 50% of respondents.

Dr. Larson noted that some motor symptoms such as tremor would not be expected to improve with exercise.

This study, the largest to date of RSB in patients with Parkinson’s disease, illustrates the benefits of this type of exercise intervention for these patients, she said.

“It’s a step in the right direction in showing that RSB, or noncontact boxing classes, can be a really good option for patients who have previously not been motivated to exercise, or maybe haven’t stuck with an exercise class, or maybe fatigue or anxiety or depression is a barrier for them to exercise.”

Patients who have experienced RSB praise its unique approach, in addition to generating friendships and promoting a sense of camaraderie and team spirit, Dr. Larson said.

“It’s almost like a support group inside an exercise class,” she noted. “We also see that people are really committed to the classes, whereas with other exercises it can be hard to get people to be motivated.”

Some 99% of current and 94% of previous participants indicated they would recommend RSB to others with Parkinson’s disease.

Interpret with caution

Commenting on the research, Michael S. Okun, MD, professor and chair of neurology, University of Florida Health, Gainesville, and medical director at the Parkinson’s Foundation, said many patients with Parkinson’s disease attend RSB classes and report that the regimen has a beneficial effect on symptoms and quality of life.

“The data from this study support these types of observations,” he said.

But Dr. Okun noted that caution is in order. “We should be careful not to overinterpret the results given that the methodology was survey-based,” he said.

To some extent, the results aren’t surprising, as multiple studies have already shown that exercise improves Parkinson’s disease symptoms and quality of life, Dr. Okun said. “We have no reason to believe that Rock Steady Boxing would not result in similar improvements.”

He stressed that a follow-up study will be necessary to better understand the potential benefits, both nonmotor and motor.

Also commenting, movement disorders specialist Anna DePold Hohler, MD, professor of neurology at Tufts University School of Medicine, Boston, and chair of neurology at St. Elizabeth’s Medical Center in Brighton, Massachusetts, said the new results “provide an added incentive” for patients to participate in RSB programs.

Such programs “should be started early and maintained,” Dr. Hohler added.

The study received no outside funding. The study authors have disclosed no relevant financial relationships. Drs. Okun and Hohler have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Boxing may help improve common nonmotor symptoms of Parkinson’s disease, new research suggests. In the study, patients with Parkinson’s disease who participated in a noncontact boxing program experienced improvement in nonmotor symptoms such as fatigue, depression, and anxiety, and had significantly better quality of life compared with their counterparts who did not engage in this type of exercise.

“We know we should be prescribing exercise for our Parkinson’s disease patients because more and more research shows it can delay the progression of the disease, but it can be overwhelming to know what type of exercise to prescribe to patients,” study investigator Danielle Larson, MD, a neurologist and movement disorders fellow at Northwestern University, Chicago, Illinois, told Medscape Medical News.

On a daily basis, patients at Dr. Larson’s clinic who have taken Rock Steady Boxing (RSB) classes “really endorse” this exercise, she said.

The findings were released March 4 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
 

Global program

A form of noncontact boxing, RSB was created in 2006 for patients with Parkinson’s disease. A typical 90-minute class starts with stretching and cardiovascular exercises, then foot movements and stepping over obstacles.

“Parkinson’s disease patients are slowed down and have difficulty navigating around obstacles,” Dr. Larson noted.

The class also includes “speed training,” such as fast walking or running. In the boxing part of the class, participants use suspended punching bags.

Dr. Larson said the RSB program caters to all patients with Parkinson’s disease, “even those who need a walker for assistance.” Most RSB sites require a release from a physician to ensure patient safety, she said.

There are now about 43,500 participants at 871 RSB sites around the world.

Adults with Parkinson’s disease who were aware of RSB completed a 20-minute anonymous survey, distributed via email and social media by RSB Inc and the Parkinson Foundation.

Of 2,054 survey respondents, 1,709 were eligible for analysis. Of these, 1,333 were currently participating in RSB, 166 had previously participated, and 210 had never participated in the program.

For all three groups, researchers gathered demographic information, such as age, gender, and income, and asked respondents how long they had the condition, who takes care of their illness, etc.

Current and previous RSB participants were asked about the exercise. For example, they were asked how many classes on average they would take per week and whether specific symptoms had improved or not changed with their participation.

RSB participants had a mean age of 69 years, 59% were male, and 96% were white. Demographics were similar for the other groups, although Dr. Larson noted that the group that had never participated was relatively small.

There was no difference between the groups in terms of years since Parkinson’ disease diagnosis or use of a movement disorders specialist.

Less fatigue

Compared with nonparticipants, a higher percentage of participants were retired (76% vs. 65%, P < .01) and married/had a partner (85% vs. 80%, P = .03).

The symptoms for which participants reported at least a 50% improvement were mostly nonmotor symptoms. For example, participants had improvements in social life (70%), fatigue (63%), fear of falling (62%), depression (60%), and anxiety (59%).

More than 50% of respondents in the previous participant group also reported improvement in these symptoms, “just not to the same degree as the current participants,” Dr. Larson said.

“Those symptoms are difficult to treat in Parkinson’s disease,” she noted. “We really don’t have any good medications for those symptoms; so to report, for example, a 63% improvement in fatigue is pretty substantial.”

The survey included the Parkinson’s Disease Questionnaire–39 (PDQ-39). The questionnaire assesses factors associated with daily living, including relationships and the impact of Parkinson’s disease on functioning and well-being.

Compared with nonparticipants, current participants had better mean scores on the PDQ-39 (25 vs. 32, P < .01), which indicates better quality of life, Dr. Larson said. Previous participants had a higher (or worse) score than current participants, she added.

Largest study to date

Researchers also examined likelihood of exercising even with certain barriers, such as distance to the gym, bad weather, or fatigue using the Self Efficacy for Exercise (SEE) Scale. Current participants had better SEE scores compared with nonparticipants (54 vs. 48, P < .01).

“We can’t prove causality. We can’t say it was the RSB that improved their quality of life or their exercise self-efficacy, but at least there’s a correlation,” Dr. Larson said.

For the SEE, again, the previous participants had lower scores than current participants, she noted.

“An interpretation of this is that individuals who previously participated but stopped did so because they had lower exercise self-efficacy – which is the ability to self-motivate and stick with an exercise – to begin with,” she said.

As for Parkinson’s disease–related motor symptoms, the survey found some improvements. “People did report between 20% and 40% improvement on various motor symptoms,” but not more than 50% of respondents.

Dr. Larson noted that some motor symptoms such as tremor would not be expected to improve with exercise.

This study, the largest to date of RSB in patients with Parkinson’s disease, illustrates the benefits of this type of exercise intervention for these patients, she said.

“It’s a step in the right direction in showing that RSB, or noncontact boxing classes, can be a really good option for patients who have previously not been motivated to exercise, or maybe haven’t stuck with an exercise class, or maybe fatigue or anxiety or depression is a barrier for them to exercise.”

Patients who have experienced RSB praise its unique approach, in addition to generating friendships and promoting a sense of camaraderie and team spirit, Dr. Larson said.

“It’s almost like a support group inside an exercise class,” she noted. “We also see that people are really committed to the classes, whereas with other exercises it can be hard to get people to be motivated.”

Some 99% of current and 94% of previous participants indicated they would recommend RSB to others with Parkinson’s disease.

Interpret with caution

Commenting on the research, Michael S. Okun, MD, professor and chair of neurology, University of Florida Health, Gainesville, and medical director at the Parkinson’s Foundation, said many patients with Parkinson’s disease attend RSB classes and report that the regimen has a beneficial effect on symptoms and quality of life.

“The data from this study support these types of observations,” he said.

But Dr. Okun noted that caution is in order. “We should be careful not to overinterpret the results given that the methodology was survey-based,” he said.

To some extent, the results aren’t surprising, as multiple studies have already shown that exercise improves Parkinson’s disease symptoms and quality of life, Dr. Okun said. “We have no reason to believe that Rock Steady Boxing would not result in similar improvements.”

He stressed that a follow-up study will be necessary to better understand the potential benefits, both nonmotor and motor.

Also commenting, movement disorders specialist Anna DePold Hohler, MD, professor of neurology at Tufts University School of Medicine, Boston, and chair of neurology at St. Elizabeth’s Medical Center in Brighton, Massachusetts, said the new results “provide an added incentive” for patients to participate in RSB programs.

Such programs “should be started early and maintained,” Dr. Hohler added.

The study received no outside funding. The study authors have disclosed no relevant financial relationships. Drs. Okun and Hohler have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Boxing may help improve common nonmotor symptoms of Parkinson’s disease, new research suggests. In the study, patients with Parkinson’s disease who participated in a noncontact boxing program experienced improvement in nonmotor symptoms such as fatigue, depression, and anxiety, and had significantly better quality of life compared with their counterparts who did not engage in this type of exercise.

“We know we should be prescribing exercise for our Parkinson’s disease patients because more and more research shows it can delay the progression of the disease, but it can be overwhelming to know what type of exercise to prescribe to patients,” study investigator Danielle Larson, MD, a neurologist and movement disorders fellow at Northwestern University, Chicago, Illinois, told Medscape Medical News.

On a daily basis, patients at Dr. Larson’s clinic who have taken Rock Steady Boxing (RSB) classes “really endorse” this exercise, she said.

The findings were released March 4 ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology. The AAN canceled the meeting and released abstracts and access to presenters for press coverage.
 

Global program

A form of noncontact boxing, RSB was created in 2006 for patients with Parkinson’s disease. A typical 90-minute class starts with stretching and cardiovascular exercises, then foot movements and stepping over obstacles.

“Parkinson’s disease patients are slowed down and have difficulty navigating around obstacles,” Dr. Larson noted.

The class also includes “speed training,” such as fast walking or running. In the boxing part of the class, participants use suspended punching bags.

Dr. Larson said the RSB program caters to all patients with Parkinson’s disease, “even those who need a walker for assistance.” Most RSB sites require a release from a physician to ensure patient safety, she said.

There are now about 43,500 participants at 871 RSB sites around the world.

Adults with Parkinson’s disease who were aware of RSB completed a 20-minute anonymous survey, distributed via email and social media by RSB Inc and the Parkinson Foundation.

Of 2,054 survey respondents, 1,709 were eligible for analysis. Of these, 1,333 were currently participating in RSB, 166 had previously participated, and 210 had never participated in the program.

For all three groups, researchers gathered demographic information, such as age, gender, and income, and asked respondents how long they had the condition, who takes care of their illness, etc.

Current and previous RSB participants were asked about the exercise. For example, they were asked how many classes on average they would take per week and whether specific symptoms had improved or not changed with their participation.

RSB participants had a mean age of 69 years, 59% were male, and 96% were white. Demographics were similar for the other groups, although Dr. Larson noted that the group that had never participated was relatively small.

There was no difference between the groups in terms of years since Parkinson’ disease diagnosis or use of a movement disorders specialist.

Less fatigue

Compared with nonparticipants, a higher percentage of participants were retired (76% vs. 65%, P < .01) and married/had a partner (85% vs. 80%, P = .03).

The symptoms for which participants reported at least a 50% improvement were mostly nonmotor symptoms. For example, participants had improvements in social life (70%), fatigue (63%), fear of falling (62%), depression (60%), and anxiety (59%).

More than 50% of respondents in the previous participant group also reported improvement in these symptoms, “just not to the same degree as the current participants,” Dr. Larson said.

“Those symptoms are difficult to treat in Parkinson’s disease,” she noted. “We really don’t have any good medications for those symptoms; so to report, for example, a 63% improvement in fatigue is pretty substantial.”

The survey included the Parkinson’s Disease Questionnaire–39 (PDQ-39). The questionnaire assesses factors associated with daily living, including relationships and the impact of Parkinson’s disease on functioning and well-being.

Compared with nonparticipants, current participants had better mean scores on the PDQ-39 (25 vs. 32, P < .01), which indicates better quality of life, Dr. Larson said. Previous participants had a higher (or worse) score than current participants, she added.

Largest study to date

Researchers also examined likelihood of exercising even with certain barriers, such as distance to the gym, bad weather, or fatigue using the Self Efficacy for Exercise (SEE) Scale. Current participants had better SEE scores compared with nonparticipants (54 vs. 48, P < .01).

“We can’t prove causality. We can’t say it was the RSB that improved their quality of life or their exercise self-efficacy, but at least there’s a correlation,” Dr. Larson said.

For the SEE, again, the previous participants had lower scores than current participants, she noted.

“An interpretation of this is that individuals who previously participated but stopped did so because they had lower exercise self-efficacy – which is the ability to self-motivate and stick with an exercise – to begin with,” she said.

As for Parkinson’s disease–related motor symptoms, the survey found some improvements. “People did report between 20% and 40% improvement on various motor symptoms,” but not more than 50% of respondents.

Dr. Larson noted that some motor symptoms such as tremor would not be expected to improve with exercise.

This study, the largest to date of RSB in patients with Parkinson’s disease, illustrates the benefits of this type of exercise intervention for these patients, she said.

“It’s a step in the right direction in showing that RSB, or noncontact boxing classes, can be a really good option for patients who have previously not been motivated to exercise, or maybe haven’t stuck with an exercise class, or maybe fatigue or anxiety or depression is a barrier for them to exercise.”

Patients who have experienced RSB praise its unique approach, in addition to generating friendships and promoting a sense of camaraderie and team spirit, Dr. Larson said.

“It’s almost like a support group inside an exercise class,” she noted. “We also see that people are really committed to the classes, whereas with other exercises it can be hard to get people to be motivated.”

Some 99% of current and 94% of previous participants indicated they would recommend RSB to others with Parkinson’s disease.

Interpret with caution

Commenting on the research, Michael S. Okun, MD, professor and chair of neurology, University of Florida Health, Gainesville, and medical director at the Parkinson’s Foundation, said many patients with Parkinson’s disease attend RSB classes and report that the regimen has a beneficial effect on symptoms and quality of life.

“The data from this study support these types of observations,” he said.

But Dr. Okun noted that caution is in order. “We should be careful not to overinterpret the results given that the methodology was survey-based,” he said.

To some extent, the results aren’t surprising, as multiple studies have already shown that exercise improves Parkinson’s disease symptoms and quality of life, Dr. Okun said. “We have no reason to believe that Rock Steady Boxing would not result in similar improvements.”

He stressed that a follow-up study will be necessary to better understand the potential benefits, both nonmotor and motor.

Also commenting, movement disorders specialist Anna DePold Hohler, MD, professor of neurology at Tufts University School of Medicine, Boston, and chair of neurology at St. Elizabeth’s Medical Center in Brighton, Massachusetts, said the new results “provide an added incentive” for patients to participate in RSB programs.

Such programs “should be started early and maintained,” Dr. Hohler added.

The study received no outside funding. The study authors have disclosed no relevant financial relationships. Drs. Okun and Hohler have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.