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People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

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

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

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

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

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

The popular antipsychotic quetiapine (Seroquel) seems to calm patients with multiple sclerosis (MS) who develop psychiatric distress after taking corticosteroids, a new case review says.

“Our case-report study observed that quetiapine was effective at decreasing irritability, reducing psychological distress, and improving sleep in patients with MS who experienced psychosis symptoms compared with patients who received no treatment. This has changed our practice as we now counsel all patients about the potential side effect of steroid-induced psychosis and discuss treatment options,” said Olinka Hrebicek, MD, medical director of Vancouver Island Multiple Sclerosis Clinic in Victoria, B.C., who was scheduled to present the study findings at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

According to Dr. Hrebicek, who spoke in an interview, nursing staff and neurologists at the Canadian clinic had typically attributed symptoms such as irritability, anger, insomnia, and psychological distress to the stress of experiencing a relapse. The treatment often was a prescription for a benzodiazepine or zopiclone.

In fact, she and colleagues wrote in their report, psychosis following treatment with high-dose corticosteroids for MS may be underreported.

“The purpose of the study was to determine whether quetiapine was effective for treating symptoms of steroid-induced psychosis in patients with MS,” study coauthor and clinic research assistant Niall Murphy said in an interview. “We also wanted to highlight the importance of looking for symptoms of steroid-induced psychosis as this is likely not the primary concern when treating patients for a relapse. In addition, nurses and neurologists may have less experience with the spectrum of clinical symptoms of psychosis than psychiatrists.”

For the case review, researchers examined 10 reports (8 female) of patients who had signs of psychiatric distress after treatment with steroids. Eight of the patients were treated with quetiapine (six female, two male).

All those who took quetiapine experienced benefits, while the two others didn’t improve.

Commenting on the study, E. Sherwood Brown, MD, PhD, MBA, professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas, said in an interview that psychosis may not appear as expected in patients who develop it as a result of corticosteroid use. “Typically, psychosis refers to delusions, hallucinations, or disorganized thought processes. However, with corticosteroids severe mood and cognitive changes [for example, delirium] are also often included in the definition. Mild mood and memory changes appear to be fairly common with prescription corticosteroids. More severe symptoms are less common.”

Higher doses of corticosteroids – like those used in MS – boost the risk of psychosis, said Dr. Brown, who was not involved in the study.

As for quetiapine, Dr. Brown said it could be a good treatment option. “The use of quetiapine, a drug approved for schizophrenia and mania, is consistent with the idea suggested in the literature that the symptoms with corticosteroids tend to be similar to those of bipolar disorder and that they respond to medications for bipolar disorder,” he said. “A potential concern is that both corticosteroids and quetiapine can cause weight gain. However, this may not be a major problem with a brief course of the corticosteroids. It would be great to see a randomized, controlled trial.”

In British Columbia, the Victoria clinic has changed policy as a result of the analysis, Dr. Hrebicek said. “Nurses and physicians now ask more specific questions to decide if patients are experiencing symptoms of steroid-induced psychosis and whether they should be treated with an antipsychotic medication.”

And now, report coauthor Mr. Murphy said, “our clinic proactively offers patients a prescription for quetiapine that they can fill if they are experiencing symptoms of steroid psychosis.”

Dr. Brown supported the new policy of alerting patients to the psychosis risk. “Counseling patients about common side effects is a good idea,” he said. “I have seen data suggesting that patients may be hesitant to report psychiatric symptoms with corticosteroids to their physicians. Letting them know about the potential for these kinds of side effects might make them more forthcoming in reporting this side effect.”

No study funding is reported. The study authors reported no disclosures. Dr. Brown has a National Institutes of Health grant for studying the effect of corticosteroids on the brain.
 

The popular antipsychotic quetiapine (Seroquel) seems to calm patients with multiple sclerosis (MS) who develop psychiatric distress after taking corticosteroids, a new case review says.

“Our case-report study observed that quetiapine was effective at decreasing irritability, reducing psychological distress, and improving sleep in patients with MS who experienced psychosis symptoms compared with patients who received no treatment. This has changed our practice as we now counsel all patients about the potential side effect of steroid-induced psychosis and discuss treatment options,” said Olinka Hrebicek, MD, medical director of Vancouver Island Multiple Sclerosis Clinic in Victoria, B.C., who was scheduled to present the study findings at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

According to Dr. Hrebicek, who spoke in an interview, nursing staff and neurologists at the Canadian clinic had typically attributed symptoms such as irritability, anger, insomnia, and psychological distress to the stress of experiencing a relapse. The treatment often was a prescription for a benzodiazepine or zopiclone.

In fact, she and colleagues wrote in their report, psychosis following treatment with high-dose corticosteroids for MS may be underreported.

“The purpose of the study was to determine whether quetiapine was effective for treating symptoms of steroid-induced psychosis in patients with MS,” study coauthor and clinic research assistant Niall Murphy said in an interview. “We also wanted to highlight the importance of looking for symptoms of steroid-induced psychosis as this is likely not the primary concern when treating patients for a relapse. In addition, nurses and neurologists may have less experience with the spectrum of clinical symptoms of psychosis than psychiatrists.”

For the case review, researchers examined 10 reports (8 female) of patients who had signs of psychiatric distress after treatment with steroids. Eight of the patients were treated with quetiapine (six female, two male).

All those who took quetiapine experienced benefits, while the two others didn’t improve.

Commenting on the study, E. Sherwood Brown, MD, PhD, MBA, professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas, said in an interview that psychosis may not appear as expected in patients who develop it as a result of corticosteroid use. “Typically, psychosis refers to delusions, hallucinations, or disorganized thought processes. However, with corticosteroids severe mood and cognitive changes [for example, delirium] are also often included in the definition. Mild mood and memory changes appear to be fairly common with prescription corticosteroids. More severe symptoms are less common.”

Higher doses of corticosteroids – like those used in MS – boost the risk of psychosis, said Dr. Brown, who was not involved in the study.

As for quetiapine, Dr. Brown said it could be a good treatment option. “The use of quetiapine, a drug approved for schizophrenia and mania, is consistent with the idea suggested in the literature that the symptoms with corticosteroids tend to be similar to those of bipolar disorder and that they respond to medications for bipolar disorder,” he said. “A potential concern is that both corticosteroids and quetiapine can cause weight gain. However, this may not be a major problem with a brief course of the corticosteroids. It would be great to see a randomized, controlled trial.”

In British Columbia, the Victoria clinic has changed policy as a result of the analysis, Dr. Hrebicek said. “Nurses and physicians now ask more specific questions to decide if patients are experiencing symptoms of steroid-induced psychosis and whether they should be treated with an antipsychotic medication.”

And now, report coauthor Mr. Murphy said, “our clinic proactively offers patients a prescription for quetiapine that they can fill if they are experiencing symptoms of steroid psychosis.”

Dr. Brown supported the new policy of alerting patients to the psychosis risk. “Counseling patients about common side effects is a good idea,” he said. “I have seen data suggesting that patients may be hesitant to report psychiatric symptoms with corticosteroids to their physicians. Letting them know about the potential for these kinds of side effects might make them more forthcoming in reporting this side effect.”

No study funding is reported. The study authors reported no disclosures. Dr. Brown has a National Institutes of Health grant for studying the effect of corticosteroids on the brain.
 

The popular antipsychotic quetiapine (Seroquel) seems to calm patients with multiple sclerosis (MS) who develop psychiatric distress after taking corticosteroids, a new case review says.

“Our case-report study observed that quetiapine was effective at decreasing irritability, reducing psychological distress, and improving sleep in patients with MS who experienced psychosis symptoms compared with patients who received no treatment. This has changed our practice as we now counsel all patients about the potential side effect of steroid-induced psychosis and discuss treatment options,” said Olinka Hrebicek, MD, medical director of Vancouver Island Multiple Sclerosis Clinic in Victoria, B.C., who was scheduled to present the study findings at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

According to Dr. Hrebicek, who spoke in an interview, nursing staff and neurologists at the Canadian clinic had typically attributed symptoms such as irritability, anger, insomnia, and psychological distress to the stress of experiencing a relapse. The treatment often was a prescription for a benzodiazepine or zopiclone.

In fact, she and colleagues wrote in their report, psychosis following treatment with high-dose corticosteroids for MS may be underreported.

“The purpose of the study was to determine whether quetiapine was effective for treating symptoms of steroid-induced psychosis in patients with MS,” study coauthor and clinic research assistant Niall Murphy said in an interview. “We also wanted to highlight the importance of looking for symptoms of steroid-induced psychosis as this is likely not the primary concern when treating patients for a relapse. In addition, nurses and neurologists may have less experience with the spectrum of clinical symptoms of psychosis than psychiatrists.”

For the case review, researchers examined 10 reports (8 female) of patients who had signs of psychiatric distress after treatment with steroids. Eight of the patients were treated with quetiapine (six female, two male).

All those who took quetiapine experienced benefits, while the two others didn’t improve.

Commenting on the study, E. Sherwood Brown, MD, PhD, MBA, professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas, said in an interview that psychosis may not appear as expected in patients who develop it as a result of corticosteroid use. “Typically, psychosis refers to delusions, hallucinations, or disorganized thought processes. However, with corticosteroids severe mood and cognitive changes [for example, delirium] are also often included in the definition. Mild mood and memory changes appear to be fairly common with prescription corticosteroids. More severe symptoms are less common.”

Higher doses of corticosteroids – like those used in MS – boost the risk of psychosis, said Dr. Brown, who was not involved in the study.

As for quetiapine, Dr. Brown said it could be a good treatment option. “The use of quetiapine, a drug approved for schizophrenia and mania, is consistent with the idea suggested in the literature that the symptoms with corticosteroids tend to be similar to those of bipolar disorder and that they respond to medications for bipolar disorder,” he said. “A potential concern is that both corticosteroids and quetiapine can cause weight gain. However, this may not be a major problem with a brief course of the corticosteroids. It would be great to see a randomized, controlled trial.”

In British Columbia, the Victoria clinic has changed policy as a result of the analysis, Dr. Hrebicek said. “Nurses and physicians now ask more specific questions to decide if patients are experiencing symptoms of steroid-induced psychosis and whether they should be treated with an antipsychotic medication.”

And now, report coauthor Mr. Murphy said, “our clinic proactively offers patients a prescription for quetiapine that they can fill if they are experiencing symptoms of steroid psychosis.”

Dr. Brown supported the new policy of alerting patients to the psychosis risk. “Counseling patients about common side effects is a good idea,” he said. “I have seen data suggesting that patients may be hesitant to report psychiatric symptoms with corticosteroids to their physicians. Letting them know about the potential for these kinds of side effects might make them more forthcoming in reporting this side effect.”

No study funding is reported. The study authors reported no disclosures. Dr. Brown has a National Institutes of Health grant for studying the effect of corticosteroids on the brain.
 

Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.

©Thinkstock

After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.

These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.

“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.

If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

Noteworthy limitations

Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.

She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.

These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”

Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.

Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
 

Replication needed

Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.

Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.

They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.

The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.

A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.

The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.

“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
 

New and important hypothesis?

Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”

He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.

However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.

He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.

It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.

“If a seemingly dangerous symptom would be happening as a result of one of these medications, it is quite surprising that it has not been noticed sooner,” he said.

Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”

The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.

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

Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.

©Thinkstock

After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.

These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.

“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.

If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

Noteworthy limitations

Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.

She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.

These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”

Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.

Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
 

Replication needed

Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.

Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.

They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.

The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.

A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.

The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.

“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
 

New and important hypothesis?

Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”

He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.

However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.

He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.

It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.

“If a seemingly dangerous symptom would be happening as a result of one of these medications, it is quite surprising that it has not been noticed sooner,” he said.

Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”

The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.

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

Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.

©Thinkstock

After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.

These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.

“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.

If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

Noteworthy limitations

Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.

She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.

These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”

Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.

Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
 

Replication needed

Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.

Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.

They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.

The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.

A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.

The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.

“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
 

New and important hypothesis?

Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”

He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.

However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.

He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.

It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.

“If a seemingly dangerous symptom would be happening as a result of one of these medications, it is quite surprising that it has not been noticed sooner,” he said.

Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”

The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.

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

Autologous hematopoietic stem cell transplantation for the treatment of active secondary progressive multiple sclerosis (MS) is associated with better disability outcomes than other immunotherapies, a new Italian study suggests.

In the study, stem cell transplant was associated with a slowing of disability progression and a higher likelihood of disability improvement in patients with secondary progressive MS compared with other disease-modifying therapies.

“Our study shows that, although limited, sustained disability improvement is still possible during early active secondary progressive MS and seems to be more likely with stem cell transplant than other disease-modifying treatments,” said lead author Giacomo Boffa, MD, University of Genoa, Italy.

“Brain penetrating–intent immune suppression in long-term immunological reconstitution within the central nervous system could be responsible for this clinical efficacy,” he added.

Dr. Boffa presented the research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He explained that compartmentalized inflation in the brain parenchyma, left meninges, and the cerebral spinal fluid (CSF) is a key driver of disability worsening in secondary progressive MS.

Although initial studies did not reveal an effect of disease-modifying therapies in secondary progressive MS, recent randomized trials have established some benefit of siponimod in reducing the risk of disability worsening, and consistent with this finding, observational studies have suggested that other available immunotherapies may also be beneficial for active secondary progressive MS, Dr. Boffa noted.

“Autologous hematopoietic stem cell transplantation has been widely investigated for the treatment of refractory MS, and although the ideal candidate for this procedure is a young patient with relapsing-remitting MS, there is some evidence to suggest that the procedure could also slow down neurological disability in patients with secondary progressive MS,” Dr. Boffa said.

“Indeed, all the drugs used in the transplant technology share the ability to cross the blood-brain barrier and exert a strong immunosuppressant effect within the brain parenchyma and CSF,” he added.  
 

Comparing treatment regimens

The aim of the current study was to compare the effect of autologous hematopoietic stem cell transplantation with other immunotherapies on disability worsening in patients with active secondary progressive MS.

Study endpoints included the Expanded Disability Status Scale (EDSS) score, 6-month worsening and improvement in disability, and sustained disability improvement over time.

The researchers studied patients with secondary progressive MS who had received autologous hematopoietic stem cell transplantation and were included in the Italian Bone Marrow Transplant Group. They were compared with a control group of patients in the Italian MS registry who had started a nontransplant disease-modifying therapy after the diagnosis of secondary progressive MS.

To control for many different variables, two separate analyses were preformed. One analyses was a propensity-score approach (patients were matched based on their propensity to receive bone marrow transplant or one of the other disease-modifying therapies). The other analysis used an overlap weighting approach (each patient was given a weight proportional to the probability of them belonging to the other treatment group).

The final cohort consisted of 79 bone marrow transplant recipients and 1,975 patients who had received other disease-modifying therapies.

Before matching, patients in the control group were older, had a longer disease duration, and had a lower annualized relapse rate than transplanted patients.

After propensity-score matching, there were 69 transplanted patients and 217 control patients who were well balanced in terms of clinical and demographic characteristics. After overlap weighting, the entire cohort was also well balanced for these variables.

In terms of the primary endpoint, stem cell transplant stabilized the EDSS score over time, while patients treated with other disease-modifying therapies had continuous progression of the EDSS score over time.

In the propensity-matched analysis, the EDSS score improved by 0.013 points per year in the stem cell transplant group compared with a worsening of 0.157 points per year in the control group. Similar results were seen in the overlap-weighting analysis.  

The effect of stem cell transplant on EDSS score translated into a significantly delayed time to confirmed disability progression in the stem cell transplant group compared with the control group (HR, 0.5; P = .005), Dr. Boffa reported.

Five years after the procedure, 62% of the transplant group were free of disability progression, compared with around 20% of the control group.  

Patients in the transplanted group were also more likely to show disability improvement over time. Five years after the procedure, almost 20% of the stem cell transplant group still maintained a disability improvement compared with only 4% of patients treated with other disease-modifying therapies.

“Our study population was composed of relatively young patients (average age 38 years) with clinical activity during secondary progressive MS, and the results of this study would not be applicable to patients with secondary progressive MS patients without signs of inflammatory activity,” Dr. Boffa commented.

“But on the other hand, our results reinforce the notion that ongoing inflammation during progressive MS requires adequate immunotherapy,” he added.   

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

Autologous hematopoietic stem cell transplantation for the treatment of active secondary progressive multiple sclerosis (MS) is associated with better disability outcomes than other immunotherapies, a new Italian study suggests.

In the study, stem cell transplant was associated with a slowing of disability progression and a higher likelihood of disability improvement in patients with secondary progressive MS compared with other disease-modifying therapies.

“Our study shows that, although limited, sustained disability improvement is still possible during early active secondary progressive MS and seems to be more likely with stem cell transplant than other disease-modifying treatments,” said lead author Giacomo Boffa, MD, University of Genoa, Italy.

“Brain penetrating–intent immune suppression in long-term immunological reconstitution within the central nervous system could be responsible for this clinical efficacy,” he added.

Dr. Boffa presented the research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He explained that compartmentalized inflation in the brain parenchyma, left meninges, and the cerebral spinal fluid (CSF) is a key driver of disability worsening in secondary progressive MS.

Although initial studies did not reveal an effect of disease-modifying therapies in secondary progressive MS, recent randomized trials have established some benefit of siponimod in reducing the risk of disability worsening, and consistent with this finding, observational studies have suggested that other available immunotherapies may also be beneficial for active secondary progressive MS, Dr. Boffa noted.

“Autologous hematopoietic stem cell transplantation has been widely investigated for the treatment of refractory MS, and although the ideal candidate for this procedure is a young patient with relapsing-remitting MS, there is some evidence to suggest that the procedure could also slow down neurological disability in patients with secondary progressive MS,” Dr. Boffa said.

“Indeed, all the drugs used in the transplant technology share the ability to cross the blood-brain barrier and exert a strong immunosuppressant effect within the brain parenchyma and CSF,” he added.  
 

Comparing treatment regimens

The aim of the current study was to compare the effect of autologous hematopoietic stem cell transplantation with other immunotherapies on disability worsening in patients with active secondary progressive MS.

Study endpoints included the Expanded Disability Status Scale (EDSS) score, 6-month worsening and improvement in disability, and sustained disability improvement over time.

The researchers studied patients with secondary progressive MS who had received autologous hematopoietic stem cell transplantation and were included in the Italian Bone Marrow Transplant Group. They were compared with a control group of patients in the Italian MS registry who had started a nontransplant disease-modifying therapy after the diagnosis of secondary progressive MS.

To control for many different variables, two separate analyses were preformed. One analyses was a propensity-score approach (patients were matched based on their propensity to receive bone marrow transplant or one of the other disease-modifying therapies). The other analysis used an overlap weighting approach (each patient was given a weight proportional to the probability of them belonging to the other treatment group).

The final cohort consisted of 79 bone marrow transplant recipients and 1,975 patients who had received other disease-modifying therapies.

Before matching, patients in the control group were older, had a longer disease duration, and had a lower annualized relapse rate than transplanted patients.

After propensity-score matching, there were 69 transplanted patients and 217 control patients who were well balanced in terms of clinical and demographic characteristics. After overlap weighting, the entire cohort was also well balanced for these variables.

In terms of the primary endpoint, stem cell transplant stabilized the EDSS score over time, while patients treated with other disease-modifying therapies had continuous progression of the EDSS score over time.

In the propensity-matched analysis, the EDSS score improved by 0.013 points per year in the stem cell transplant group compared with a worsening of 0.157 points per year in the control group. Similar results were seen in the overlap-weighting analysis.  

The effect of stem cell transplant on EDSS score translated into a significantly delayed time to confirmed disability progression in the stem cell transplant group compared with the control group (HR, 0.5; P = .005), Dr. Boffa reported.

Five years after the procedure, 62% of the transplant group were free of disability progression, compared with around 20% of the control group.  

Patients in the transplanted group were also more likely to show disability improvement over time. Five years after the procedure, almost 20% of the stem cell transplant group still maintained a disability improvement compared with only 4% of patients treated with other disease-modifying therapies.

“Our study population was composed of relatively young patients (average age 38 years) with clinical activity during secondary progressive MS, and the results of this study would not be applicable to patients with secondary progressive MS patients without signs of inflammatory activity,” Dr. Boffa commented.

“But on the other hand, our results reinforce the notion that ongoing inflammation during progressive MS requires adequate immunotherapy,” he added.   

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

Autologous hematopoietic stem cell transplantation for the treatment of active secondary progressive multiple sclerosis (MS) is associated with better disability outcomes than other immunotherapies, a new Italian study suggests.

In the study, stem cell transplant was associated with a slowing of disability progression and a higher likelihood of disability improvement in patients with secondary progressive MS compared with other disease-modifying therapies.

“Our study shows that, although limited, sustained disability improvement is still possible during early active secondary progressive MS and seems to be more likely with stem cell transplant than other disease-modifying treatments,” said lead author Giacomo Boffa, MD, University of Genoa, Italy.

“Brain penetrating–intent immune suppression in long-term immunological reconstitution within the central nervous system could be responsible for this clinical efficacy,” he added.

Dr. Boffa presented the research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He explained that compartmentalized inflation in the brain parenchyma, left meninges, and the cerebral spinal fluid (CSF) is a key driver of disability worsening in secondary progressive MS.

Although initial studies did not reveal an effect of disease-modifying therapies in secondary progressive MS, recent randomized trials have established some benefit of siponimod in reducing the risk of disability worsening, and consistent with this finding, observational studies have suggested that other available immunotherapies may also be beneficial for active secondary progressive MS, Dr. Boffa noted.

“Autologous hematopoietic stem cell transplantation has been widely investigated for the treatment of refractory MS, and although the ideal candidate for this procedure is a young patient with relapsing-remitting MS, there is some evidence to suggest that the procedure could also slow down neurological disability in patients with secondary progressive MS,” Dr. Boffa said.

“Indeed, all the drugs used in the transplant technology share the ability to cross the blood-brain barrier and exert a strong immunosuppressant effect within the brain parenchyma and CSF,” he added.  
 

Comparing treatment regimens

The aim of the current study was to compare the effect of autologous hematopoietic stem cell transplantation with other immunotherapies on disability worsening in patients with active secondary progressive MS.

Study endpoints included the Expanded Disability Status Scale (EDSS) score, 6-month worsening and improvement in disability, and sustained disability improvement over time.

The researchers studied patients with secondary progressive MS who had received autologous hematopoietic stem cell transplantation and were included in the Italian Bone Marrow Transplant Group. They were compared with a control group of patients in the Italian MS registry who had started a nontransplant disease-modifying therapy after the diagnosis of secondary progressive MS.

To control for many different variables, two separate analyses were preformed. One analyses was a propensity-score approach (patients were matched based on their propensity to receive bone marrow transplant or one of the other disease-modifying therapies). The other analysis used an overlap weighting approach (each patient was given a weight proportional to the probability of them belonging to the other treatment group).

The final cohort consisted of 79 bone marrow transplant recipients and 1,975 patients who had received other disease-modifying therapies.

Before matching, patients in the control group were older, had a longer disease duration, and had a lower annualized relapse rate than transplanted patients.

After propensity-score matching, there were 69 transplanted patients and 217 control patients who were well balanced in terms of clinical and demographic characteristics. After overlap weighting, the entire cohort was also well balanced for these variables.

In terms of the primary endpoint, stem cell transplant stabilized the EDSS score over time, while patients treated with other disease-modifying therapies had continuous progression of the EDSS score over time.

In the propensity-matched analysis, the EDSS score improved by 0.013 points per year in the stem cell transplant group compared with a worsening of 0.157 points per year in the control group. Similar results were seen in the overlap-weighting analysis.  

The effect of stem cell transplant on EDSS score translated into a significantly delayed time to confirmed disability progression in the stem cell transplant group compared with the control group (HR, 0.5; P = .005), Dr. Boffa reported.

Five years after the procedure, 62% of the transplant group were free of disability progression, compared with around 20% of the control group.  

Patients in the transplanted group were also more likely to show disability improvement over time. Five years after the procedure, almost 20% of the stem cell transplant group still maintained a disability improvement compared with only 4% of patients treated with other disease-modifying therapies.

“Our study population was composed of relatively young patients (average age 38 years) with clinical activity during secondary progressive MS, and the results of this study would not be applicable to patients with secondary progressive MS patients without signs of inflammatory activity,” Dr. Boffa commented.

“But on the other hand, our results reinforce the notion that ongoing inflammation during progressive MS requires adequate immunotherapy,” he added.   

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

Updated European guidelines on the treatment of patients with multiple sclerosis (MS) have been announced and include a recommendation for siponimod (Mayzent) in progressive MS, as well as a general emphasis toward earlier and more aggressive treatment.

The updated guidelines were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and are the result of a collaboration between ECTRIMS and the European Academy of Neurology (EAN).

Maria Pia Amato, MD, ECTRIMS president and co-chair of the guidelines steering committee, noted that the European MS treatment guidelines were last published in 2018. “Since then more trials have been published, and we felt this was a good time to incorporate the new evidence into updated guidelines,” she said.

“As before, the updated guidelines contain a number of core questions that address the efficacy of disease-modifying therapies, early treatment decisions, disease/treatment response monitoring and treatment modifications, treatment suspension and disease reactivation, and pregnancy and breastfeeding,” Dr. Amato said.
 

New recommendations

New features of the updated guidelines include a recommendation for siponimod for secondary progressive MS with evidence of disease inflammatory activity; in addition, there is more emphasis on starting treatment early, with greater consideration of higher efficacy drugs, depending on the characteristics of the disease and the patient, Dr. Amato commented.

“We also provided more detailed information on disease-modifying therapy use in pregnancy and breastfeeding and also for women with high disease activity who desire to become pregnant,” she added.

Other new features include the introduction of clinical questions dealing with treatment safety and monitoring (for example, for natalizumab) and also considering the current COVID-19 pandemic scenario; switching strategies with more detailed practical indications on timing; and long lasting effects of drugs such as alemtuzumab and cladribine, Dr. Amato said.

The updated guidelines include the following recommendations:

• The entire spectrum of disease-modifying drugs should be prescribed by a neurologist with expertise in MS and ready access to adequate infrastructure to provide proper monitoring of patents, comprehensive assessment, early detection of side effects, and the capacity to address those side effects promptly.
• Offer interferon or glatiramer acetate to patients with clinically isolated syndrome (CIS) highly suggestive of MS and an abnormal MRI with lesions suggestive of MS who do not fulfill criteria for MS.
• For patients with relapsing-remitting MS, the choice between a wide range of available drugs (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, ozanimod, ponesimod, natalizumab, alemtuzumab, ocrelizumab, rituximab, or ofatumumab), from modestly to highly effective, will depend on factors including: underlying disability progression, disease severity/clinical or radiological activity, patient characteristics and morbidity, drug safety profile, family planning, and patient preferences.

Progressive MS

• For patients with secondary progressive MS with evidence of inflammatory activity (relapses and/or MRI activity), offer treatment with siponimod. Treatment with other therapies used for relapsing remitting MS may also be considered.
• For secondary progressive MS without evidence of inflammatory activity, particularly in young patients and those in whom progression has started recently, consider treatment with siponimod or anti-CD20 monoclonal antibodies, taking into account that there is scarce evidence to support their use in this setting.  
• For patients with active secondary progressive MS when there is no other therapy available, consider treatment with mitoxantrone, taking into account the safety concerns and tolerability issues of this agent. 
• Consider ocrelizumab for patients with primary progressive MS, particularly early and active (clinically and/or radiologically) disease.

Emphasis toward higher-efficacy drugs

• Consider choosing a higher-efficacy disease-modifying drug early on, according to disease activity (either clinically or on MRI).
• Offer a more efficacious drug to patients who show evidence of disease activity with their current treatment.
• When treatment with a high-efficacy drug is stopped, whether because of inefficacy or risk of adverse effects, consider starting another high-efficacy drug, taking into account clinical and MRI disease activity before and during treatment, pharmacokinetics and biological activity of the previous drug, and the potential for resumed disease activity or even rebound syndrome (particularly with natalizumab and S1P modulators).
• In the stable patient (clinically and on MRI) who shows no safety or tolerability issues, consider continuing treatment with disease-modifying therapy, taking into account patient characteristics and comorbidities, drug safety profile, family planning, and patient preferences.

Recommendations for pregnancy and breastfeeding

Recommendations for pregnant women and mothers who choose to breastfeed include:

• Advise women who wish to become pregnant to plan their pregnancy beforehand.
• Advise women of childbearing potential that MS disease-modifying therapies are not licensed during pregnancy, with the exception of interferons and glatiramer acetate.
• For women planning a pregnancy, offer interferons and glatiramer acetate and consider continuing these agents during pregnancy after assessment of risk and benefits. Consider using dimethyl fumarate until pregnancy is confirmed and stopping during pregnancy after assessment of the risks and benefits. 
• For women with highly active disease who wish to become pregnant, there are a number of therapeutic options:

1)  treatment with long lasting effects such as alemtuzumab or cladribine provided that at least 4 or 6 months respectively have elapsed between the last dose and conception2)  treatment with anti-CD20 drugs before pregnancy with advice to wait for 2-6 months after the last infusion before becoming pregnant and to avoid further infusions during pregnancy, or3) for patients treated with natalizumab, consider continuing treatment during pregnancy using a 6-week extended dosage regimen until the end of the second trimester or up until week 34 and resuming after delivery (in newborns exposed to natalizumab, check for hematological abnormalities and liver function)

• Only interferons and ofatumumab are currently approved during breastfeeding.   
•  

Treatment safety/monitoring

• When treating patients with natalizumab and after a period of stability, consider switching to a 6-week interval regimen in order to minimize the risk of progressive multifocal leukoencephalopathy (PML).
• Consider treatment with high-efficacy drugs including natalizumab in patients with high disease activity, in whom a quick therapeutic effect is required, taking into account the risk of PML in John Cunningham virus (JCV)-positive patients, as well as the therapeutic lag of the different disease-modifying drugs.
• Ideally, prioritize vaccination against COVID-19 before starting immunosuppressive disease-modifying treatments to achieve the highest protection rate possible.
•  

Long-lasting treatments

• When using long-lasting treatments (alemtuzumab or cladribine) in patients who experience disease activity before the treatment is completed (between the first and second cycles), consider waiting until completion of the therapeutic regimen before switching to other drugs.
• Consider offering additional courses of alemtuzumab after the first two cycles at least 1 year apart from each other when disease activity has not remitted completely or reappears after a period of stability, taking into account the balance between the potential benefits and side effects.

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

Updated European guidelines on the treatment of patients with multiple sclerosis (MS) have been announced and include a recommendation for siponimod (Mayzent) in progressive MS, as well as a general emphasis toward earlier and more aggressive treatment.

The updated guidelines were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and are the result of a collaboration between ECTRIMS and the European Academy of Neurology (EAN).

Maria Pia Amato, MD, ECTRIMS president and co-chair of the guidelines steering committee, noted that the European MS treatment guidelines were last published in 2018. “Since then more trials have been published, and we felt this was a good time to incorporate the new evidence into updated guidelines,” she said.

“As before, the updated guidelines contain a number of core questions that address the efficacy of disease-modifying therapies, early treatment decisions, disease/treatment response monitoring and treatment modifications, treatment suspension and disease reactivation, and pregnancy and breastfeeding,” Dr. Amato said.
 

New recommendations

New features of the updated guidelines include a recommendation for siponimod for secondary progressive MS with evidence of disease inflammatory activity; in addition, there is more emphasis on starting treatment early, with greater consideration of higher efficacy drugs, depending on the characteristics of the disease and the patient, Dr. Amato commented.

“We also provided more detailed information on disease-modifying therapy use in pregnancy and breastfeeding and also for women with high disease activity who desire to become pregnant,” she added.

Other new features include the introduction of clinical questions dealing with treatment safety and monitoring (for example, for natalizumab) and also considering the current COVID-19 pandemic scenario; switching strategies with more detailed practical indications on timing; and long lasting effects of drugs such as alemtuzumab and cladribine, Dr. Amato said.

The updated guidelines include the following recommendations:

• The entire spectrum of disease-modifying drugs should be prescribed by a neurologist with expertise in MS and ready access to adequate infrastructure to provide proper monitoring of patents, comprehensive assessment, early detection of side effects, and the capacity to address those side effects promptly.
• Offer interferon or glatiramer acetate to patients with clinically isolated syndrome (CIS) highly suggestive of MS and an abnormal MRI with lesions suggestive of MS who do not fulfill criteria for MS.
• For patients with relapsing-remitting MS, the choice between a wide range of available drugs (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, ozanimod, ponesimod, natalizumab, alemtuzumab, ocrelizumab, rituximab, or ofatumumab), from modestly to highly effective, will depend on factors including: underlying disability progression, disease severity/clinical or radiological activity, patient characteristics and morbidity, drug safety profile, family planning, and patient preferences.

Progressive MS

• For patients with secondary progressive MS with evidence of inflammatory activity (relapses and/or MRI activity), offer treatment with siponimod. Treatment with other therapies used for relapsing remitting MS may also be considered.
• For secondary progressive MS without evidence of inflammatory activity, particularly in young patients and those in whom progression has started recently, consider treatment with siponimod or anti-CD20 monoclonal antibodies, taking into account that there is scarce evidence to support their use in this setting.  
• For patients with active secondary progressive MS when there is no other therapy available, consider treatment with mitoxantrone, taking into account the safety concerns and tolerability issues of this agent. 
• Consider ocrelizumab for patients with primary progressive MS, particularly early and active (clinically and/or radiologically) disease.

Emphasis toward higher-efficacy drugs

• Consider choosing a higher-efficacy disease-modifying drug early on, according to disease activity (either clinically or on MRI).
• Offer a more efficacious drug to patients who show evidence of disease activity with their current treatment.
• When treatment with a high-efficacy drug is stopped, whether because of inefficacy or risk of adverse effects, consider starting another high-efficacy drug, taking into account clinical and MRI disease activity before and during treatment, pharmacokinetics and biological activity of the previous drug, and the potential for resumed disease activity or even rebound syndrome (particularly with natalizumab and S1P modulators).
• In the stable patient (clinically and on MRI) who shows no safety or tolerability issues, consider continuing treatment with disease-modifying therapy, taking into account patient characteristics and comorbidities, drug safety profile, family planning, and patient preferences.

Recommendations for pregnancy and breastfeeding

Recommendations for pregnant women and mothers who choose to breastfeed include:

• Advise women who wish to become pregnant to plan their pregnancy beforehand.
• Advise women of childbearing potential that MS disease-modifying therapies are not licensed during pregnancy, with the exception of interferons and glatiramer acetate.
• For women planning a pregnancy, offer interferons and glatiramer acetate and consider continuing these agents during pregnancy after assessment of risk and benefits. Consider using dimethyl fumarate until pregnancy is confirmed and stopping during pregnancy after assessment of the risks and benefits. 
• For women with highly active disease who wish to become pregnant, there are a number of therapeutic options:

1)  treatment with long lasting effects such as alemtuzumab or cladribine provided that at least 4 or 6 months respectively have elapsed between the last dose and conception2)  treatment with anti-CD20 drugs before pregnancy with advice to wait for 2-6 months after the last infusion before becoming pregnant and to avoid further infusions during pregnancy, or3) for patients treated with natalizumab, consider continuing treatment during pregnancy using a 6-week extended dosage regimen until the end of the second trimester or up until week 34 and resuming after delivery (in newborns exposed to natalizumab, check for hematological abnormalities and liver function)

• Only interferons and ofatumumab are currently approved during breastfeeding.   
•  

Treatment safety/monitoring

• When treating patients with natalizumab and after a period of stability, consider switching to a 6-week interval regimen in order to minimize the risk of progressive multifocal leukoencephalopathy (PML).
• Consider treatment with high-efficacy drugs including natalizumab in patients with high disease activity, in whom a quick therapeutic effect is required, taking into account the risk of PML in John Cunningham virus (JCV)-positive patients, as well as the therapeutic lag of the different disease-modifying drugs.
• Ideally, prioritize vaccination against COVID-19 before starting immunosuppressive disease-modifying treatments to achieve the highest protection rate possible.
•  

Long-lasting treatments

• When using long-lasting treatments (alemtuzumab or cladribine) in patients who experience disease activity before the treatment is completed (between the first and second cycles), consider waiting until completion of the therapeutic regimen before switching to other drugs.
• Consider offering additional courses of alemtuzumab after the first two cycles at least 1 year apart from each other when disease activity has not remitted completely or reappears after a period of stability, taking into account the balance between the potential benefits and side effects.

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

Updated European guidelines on the treatment of patients with multiple sclerosis (MS) have been announced and include a recommendation for siponimod (Mayzent) in progressive MS, as well as a general emphasis toward earlier and more aggressive treatment.

The updated guidelines were presented at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and are the result of a collaboration between ECTRIMS and the European Academy of Neurology (EAN).

Maria Pia Amato, MD, ECTRIMS president and co-chair of the guidelines steering committee, noted that the European MS treatment guidelines were last published in 2018. “Since then more trials have been published, and we felt this was a good time to incorporate the new evidence into updated guidelines,” she said.

“As before, the updated guidelines contain a number of core questions that address the efficacy of disease-modifying therapies, early treatment decisions, disease/treatment response monitoring and treatment modifications, treatment suspension and disease reactivation, and pregnancy and breastfeeding,” Dr. Amato said.
 

New recommendations

New features of the updated guidelines include a recommendation for siponimod for secondary progressive MS with evidence of disease inflammatory activity; in addition, there is more emphasis on starting treatment early, with greater consideration of higher efficacy drugs, depending on the characteristics of the disease and the patient, Dr. Amato commented.

“We also provided more detailed information on disease-modifying therapy use in pregnancy and breastfeeding and also for women with high disease activity who desire to become pregnant,” she added.

Other new features include the introduction of clinical questions dealing with treatment safety and monitoring (for example, for natalizumab) and also considering the current COVID-19 pandemic scenario; switching strategies with more detailed practical indications on timing; and long lasting effects of drugs such as alemtuzumab and cladribine, Dr. Amato said.

The updated guidelines include the following recommendations:

• The entire spectrum of disease-modifying drugs should be prescribed by a neurologist with expertise in MS and ready access to adequate infrastructure to provide proper monitoring of patents, comprehensive assessment, early detection of side effects, and the capacity to address those side effects promptly.
• Offer interferon or glatiramer acetate to patients with clinically isolated syndrome (CIS) highly suggestive of MS and an abnormal MRI with lesions suggestive of MS who do not fulfill criteria for MS.
• For patients with relapsing-remitting MS, the choice between a wide range of available drugs (interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, ozanimod, ponesimod, natalizumab, alemtuzumab, ocrelizumab, rituximab, or ofatumumab), from modestly to highly effective, will depend on factors including: underlying disability progression, disease severity/clinical or radiological activity, patient characteristics and morbidity, drug safety profile, family planning, and patient preferences.

Progressive MS

• For patients with secondary progressive MS with evidence of inflammatory activity (relapses and/or MRI activity), offer treatment with siponimod. Treatment with other therapies used for relapsing remitting MS may also be considered.
• For secondary progressive MS without evidence of inflammatory activity, particularly in young patients and those in whom progression has started recently, consider treatment with siponimod or anti-CD20 monoclonal antibodies, taking into account that there is scarce evidence to support their use in this setting.  
• For patients with active secondary progressive MS when there is no other therapy available, consider treatment with mitoxantrone, taking into account the safety concerns and tolerability issues of this agent. 
• Consider ocrelizumab for patients with primary progressive MS, particularly early and active (clinically and/or radiologically) disease.

Emphasis toward higher-efficacy drugs

• Consider choosing a higher-efficacy disease-modifying drug early on, according to disease activity (either clinically or on MRI).
• Offer a more efficacious drug to patients who show evidence of disease activity with their current treatment.
• When treatment with a high-efficacy drug is stopped, whether because of inefficacy or risk of adverse effects, consider starting another high-efficacy drug, taking into account clinical and MRI disease activity before and during treatment, pharmacokinetics and biological activity of the previous drug, and the potential for resumed disease activity or even rebound syndrome (particularly with natalizumab and S1P modulators).
• In the stable patient (clinically and on MRI) who shows no safety or tolerability issues, consider continuing treatment with disease-modifying therapy, taking into account patient characteristics and comorbidities, drug safety profile, family planning, and patient preferences.

Recommendations for pregnancy and breastfeeding

Recommendations for pregnant women and mothers who choose to breastfeed include:

• Advise women who wish to become pregnant to plan their pregnancy beforehand.
• Advise women of childbearing potential that MS disease-modifying therapies are not licensed during pregnancy, with the exception of interferons and glatiramer acetate.
• For women planning a pregnancy, offer interferons and glatiramer acetate and consider continuing these agents during pregnancy after assessment of risk and benefits. Consider using dimethyl fumarate until pregnancy is confirmed and stopping during pregnancy after assessment of the risks and benefits. 
• For women with highly active disease who wish to become pregnant, there are a number of therapeutic options:

1)  treatment with long lasting effects such as alemtuzumab or cladribine provided that at least 4 or 6 months respectively have elapsed between the last dose and conception2)  treatment with anti-CD20 drugs before pregnancy with advice to wait for 2-6 months after the last infusion before becoming pregnant and to avoid further infusions during pregnancy, or3) for patients treated with natalizumab, consider continuing treatment during pregnancy using a 6-week extended dosage regimen until the end of the second trimester or up until week 34 and resuming after delivery (in newborns exposed to natalizumab, check for hematological abnormalities and liver function)

• Only interferons and ofatumumab are currently approved during breastfeeding.   
•  

Treatment safety/monitoring

• When treating patients with natalizumab and after a period of stability, consider switching to a 6-week interval regimen in order to minimize the risk of progressive multifocal leukoencephalopathy (PML).
• Consider treatment with high-efficacy drugs including natalizumab in patients with high disease activity, in whom a quick therapeutic effect is required, taking into account the risk of PML in John Cunningham virus (JCV)-positive patients, as well as the therapeutic lag of the different disease-modifying drugs.
• Ideally, prioritize vaccination against COVID-19 before starting immunosuppressive disease-modifying treatments to achieve the highest protection rate possible.
•  

Long-lasting treatments

• When using long-lasting treatments (alemtuzumab or cladribine) in patients who experience disease activity before the treatment is completed (between the first and second cycles), consider waiting until completion of the therapeutic regimen before switching to other drugs.
• Consider offering additional courses of alemtuzumab after the first two cycles at least 1 year apart from each other when disease activity has not remitted completely or reappears after a period of stability, taking into account the balance between the potential benefits and side effects.

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

Among pediatric patients with multiple sclerosis (MS), some specific clinical characteristics, as well as treatment with disease-modifying therapies (DMTs), are linked to less future disability.

An estimated 3%-10% of MS patients are diagnosed during childhood. These patients experience a higher relapse rate and have higher magnetic resonance imaging (MRI) activity than do adult-onset patients. They have a slower rate of progression, but they reach irreversible disability milestones at an early age, with more than 50% having secondary progressive disease by age 30.

Studies in adults suggest that use of high-efficacy DMTs is most effective when initiated during the early active phase of MS, but little is known about children. “Early recognition of predictors of faster disability in children is crucial for clinicians to make the treatment decisions at the earliest possible time,” Sifat Sharmin, PhD, said during her presentation of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Sharmin is a statistician and research fellow at the University of Melbourne.
 

‘Reassuring’ data

“I think the most important observation that was made here is the protective factor of use of high efficacy disease modifying therapies,” said Bruce Cree, MD, PhD, who was asked to comment on the study.

That result wasn’t unexpected, but it should provide reassurance. “For parents of children who are hesitant about use of high efficacy therapies, this study provides supporting evidence for use of these high efficacy therapies early on, to try and prevent irreversible disability from occurring,” said Dr. Cree, professor of clinical neurology and the George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California at San Francisco UCSF Weill Institute for Neurosciences.

The study provides real-world data to back up findings from a phase 3 clinical trial that showed fewer relapses and fewer new lesions in pediatric patients with MS who were taking fingolimod versus interferon beta-1a.

“Given a large randomized, controlled trial, and now with this additional real-world data set showing the same thing, the only conclusion to reach is that if you’ve got a kid with MS, they should be treated with fingolimod,” said Dr. Cree. He noted that other DMTs such as natalizumab may also benefit pediatric patients, but fingolimod is the only drug that has been studied in randomized, controlled trials in children.

Real-world data

The researchers analyzed data from 672 patients drawn from the international MSBase Neuroimmunology Registry, who had undergone neurological assessment within 1 year of symptom onset and had at least two annual visits where the Expanded Disability Status Scale (EDSS) was recorded. They sought to identify predictors of Multiple Sclerosis Severity Score (MSSS). A secondary analysis looked at predictors of EDSS sustained worsening at 6 months, defined as an increase of 1.5 if EDSS baseline was 0, 1.0 or more if baseline EDSS was 1.0-5.5, or 0.5 if baseline EDSS was over 5.5.

The researchers also conducted a sensitivity analysis that looked at relapse phenotypes and relapse frequency in the first year, as well as a subgroup analysis of patients with available MRI data from the first year. The researchers adjusted for time on high-efficacy DMTs at each visit.

Among the study participants, 70% were female. The median age of onset was 16 years. The median EDSS score was 1.5 at inclusion, and the median score was 1.0 at follow-up of 3 years. At 6 months, 82 worsening events occurred in 57 patients.

A total of 76% of the patients were treated with DMTs. The most commonly prescribed DMTs were interferon beta (40.63%), natalizumab (8.48%), and fingolimod (6.40%). Seventy-eight percent of those who received DMTs started treatment before age 18. Twenty-seven percent received high-efficacy DMTs.

The analysis showed associations between disability and older age at onset [exp(beta), 1.09; 95% confidence interval, 1.03-1.16], maximum EDSS score during the first year of disease [exp(beta), 1.25; 95% CI, 1.13-1.36], or first-year pyramidal symptoms [exp(beta), 1.34; 95% CI, 1.13-1.58], visual symptoms [exp(beta), 1.28; 95% CI, 1.10-1.48], or cerebellum symptoms [exp(beta), 1.17; 95% CI, 1.00-1.39]. A greater amount of time on high-efficacy DMTs was associated with a lower probability of disability [exp(beta), 0.96; 95% CI, 0.93-0.99].

A complete recovery from the first relapse was associated with a lower probability of relapse, though this association did not reach statistical significance [exp(beta), 0.83; 95% CI, 0.68-1.03].

The secondary analyses found that the only predictor of 6-month EDSS worsening [exp(beta), 1.32; 95% CI, 1.21-1.45] was having a maximum EDSS score in the first year. Sensitivity analyses of complete and incomplete recovery from relapses found that a higher MSSS was associated incomplete recovery [exp(beta), 1.16; 95% CI, 1.02-1.32], and confirmed the primary finding that recovery from first relapse was associated with a lower probability of disability [exp(beta), 0.78; 95% CI, 0.63-0.96].

Among patients with MRI data, a new MRI lesion in year 1 was associated with a lower future MSSS score [exp(beta), 0.81; 95% CI, 0.66-0.99].

The study was funded by the National Health and Medical Research Council of Australia. The study authors disclosed ties with a wide range of pharmaceutical companies, including Biogen and Novartis. Dr. Cree has consulted for Biogen, Novartis, and other pharmaceutical companies.

Among pediatric patients with multiple sclerosis (MS), some specific clinical characteristics, as well as treatment with disease-modifying therapies (DMTs), are linked to less future disability.

An estimated 3%-10% of MS patients are diagnosed during childhood. These patients experience a higher relapse rate and have higher magnetic resonance imaging (MRI) activity than do adult-onset patients. They have a slower rate of progression, but they reach irreversible disability milestones at an early age, with more than 50% having secondary progressive disease by age 30.

Studies in adults suggest that use of high-efficacy DMTs is most effective when initiated during the early active phase of MS, but little is known about children. “Early recognition of predictors of faster disability in children is crucial for clinicians to make the treatment decisions at the earliest possible time,” Sifat Sharmin, PhD, said during her presentation of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Sharmin is a statistician and research fellow at the University of Melbourne.
 

‘Reassuring’ data

“I think the most important observation that was made here is the protective factor of use of high efficacy disease modifying therapies,” said Bruce Cree, MD, PhD, who was asked to comment on the study.

That result wasn’t unexpected, but it should provide reassurance. “For parents of children who are hesitant about use of high efficacy therapies, this study provides supporting evidence for use of these high efficacy therapies early on, to try and prevent irreversible disability from occurring,” said Dr. Cree, professor of clinical neurology and the George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California at San Francisco UCSF Weill Institute for Neurosciences.

The study provides real-world data to back up findings from a phase 3 clinical trial that showed fewer relapses and fewer new lesions in pediatric patients with MS who were taking fingolimod versus interferon beta-1a.

“Given a large randomized, controlled trial, and now with this additional real-world data set showing the same thing, the only conclusion to reach is that if you’ve got a kid with MS, they should be treated with fingolimod,” said Dr. Cree. He noted that other DMTs such as natalizumab may also benefit pediatric patients, but fingolimod is the only drug that has been studied in randomized, controlled trials in children.

Real-world data

The researchers analyzed data from 672 patients drawn from the international MSBase Neuroimmunology Registry, who had undergone neurological assessment within 1 year of symptom onset and had at least two annual visits where the Expanded Disability Status Scale (EDSS) was recorded. They sought to identify predictors of Multiple Sclerosis Severity Score (MSSS). A secondary analysis looked at predictors of EDSS sustained worsening at 6 months, defined as an increase of 1.5 if EDSS baseline was 0, 1.0 or more if baseline EDSS was 1.0-5.5, or 0.5 if baseline EDSS was over 5.5.

The researchers also conducted a sensitivity analysis that looked at relapse phenotypes and relapse frequency in the first year, as well as a subgroup analysis of patients with available MRI data from the first year. The researchers adjusted for time on high-efficacy DMTs at each visit.

Among the study participants, 70% were female. The median age of onset was 16 years. The median EDSS score was 1.5 at inclusion, and the median score was 1.0 at follow-up of 3 years. At 6 months, 82 worsening events occurred in 57 patients.

A total of 76% of the patients were treated with DMTs. The most commonly prescribed DMTs were interferon beta (40.63%), natalizumab (8.48%), and fingolimod (6.40%). Seventy-eight percent of those who received DMTs started treatment before age 18. Twenty-seven percent received high-efficacy DMTs.

The analysis showed associations between disability and older age at onset [exp(beta), 1.09; 95% confidence interval, 1.03-1.16], maximum EDSS score during the first year of disease [exp(beta), 1.25; 95% CI, 1.13-1.36], or first-year pyramidal symptoms [exp(beta), 1.34; 95% CI, 1.13-1.58], visual symptoms [exp(beta), 1.28; 95% CI, 1.10-1.48], or cerebellum symptoms [exp(beta), 1.17; 95% CI, 1.00-1.39]. A greater amount of time on high-efficacy DMTs was associated with a lower probability of disability [exp(beta), 0.96; 95% CI, 0.93-0.99].

A complete recovery from the first relapse was associated with a lower probability of relapse, though this association did not reach statistical significance [exp(beta), 0.83; 95% CI, 0.68-1.03].

The secondary analyses found that the only predictor of 6-month EDSS worsening [exp(beta), 1.32; 95% CI, 1.21-1.45] was having a maximum EDSS score in the first year. Sensitivity analyses of complete and incomplete recovery from relapses found that a higher MSSS was associated incomplete recovery [exp(beta), 1.16; 95% CI, 1.02-1.32], and confirmed the primary finding that recovery from first relapse was associated with a lower probability of disability [exp(beta), 0.78; 95% CI, 0.63-0.96].

Among patients with MRI data, a new MRI lesion in year 1 was associated with a lower future MSSS score [exp(beta), 0.81; 95% CI, 0.66-0.99].

The study was funded by the National Health and Medical Research Council of Australia. The study authors disclosed ties with a wide range of pharmaceutical companies, including Biogen and Novartis. Dr. Cree has consulted for Biogen, Novartis, and other pharmaceutical companies.

Among pediatric patients with multiple sclerosis (MS), some specific clinical characteristics, as well as treatment with disease-modifying therapies (DMTs), are linked to less future disability.

An estimated 3%-10% of MS patients are diagnosed during childhood. These patients experience a higher relapse rate and have higher magnetic resonance imaging (MRI) activity than do adult-onset patients. They have a slower rate of progression, but they reach irreversible disability milestones at an early age, with more than 50% having secondary progressive disease by age 30.

Studies in adults suggest that use of high-efficacy DMTs is most effective when initiated during the early active phase of MS, but little is known about children. “Early recognition of predictors of faster disability in children is crucial for clinicians to make the treatment decisions at the earliest possible time,” Sifat Sharmin, PhD, said during her presentation of the study at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Dr. Sharmin is a statistician and research fellow at the University of Melbourne.
 

‘Reassuring’ data

“I think the most important observation that was made here is the protective factor of use of high efficacy disease modifying therapies,” said Bruce Cree, MD, PhD, who was asked to comment on the study.

That result wasn’t unexpected, but it should provide reassurance. “For parents of children who are hesitant about use of high efficacy therapies, this study provides supporting evidence for use of these high efficacy therapies early on, to try and prevent irreversible disability from occurring,” said Dr. Cree, professor of clinical neurology and the George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California at San Francisco UCSF Weill Institute for Neurosciences.

The study provides real-world data to back up findings from a phase 3 clinical trial that showed fewer relapses and fewer new lesions in pediatric patients with MS who were taking fingolimod versus interferon beta-1a.

“Given a large randomized, controlled trial, and now with this additional real-world data set showing the same thing, the only conclusion to reach is that if you’ve got a kid with MS, they should be treated with fingolimod,” said Dr. Cree. He noted that other DMTs such as natalizumab may also benefit pediatric patients, but fingolimod is the only drug that has been studied in randomized, controlled trials in children.

Real-world data

The researchers analyzed data from 672 patients drawn from the international MSBase Neuroimmunology Registry, who had undergone neurological assessment within 1 year of symptom onset and had at least two annual visits where the Expanded Disability Status Scale (EDSS) was recorded. They sought to identify predictors of Multiple Sclerosis Severity Score (MSSS). A secondary analysis looked at predictors of EDSS sustained worsening at 6 months, defined as an increase of 1.5 if EDSS baseline was 0, 1.0 or more if baseline EDSS was 1.0-5.5, or 0.5 if baseline EDSS was over 5.5.

The researchers also conducted a sensitivity analysis that looked at relapse phenotypes and relapse frequency in the first year, as well as a subgroup analysis of patients with available MRI data from the first year. The researchers adjusted for time on high-efficacy DMTs at each visit.

Among the study participants, 70% were female. The median age of onset was 16 years. The median EDSS score was 1.5 at inclusion, and the median score was 1.0 at follow-up of 3 years. At 6 months, 82 worsening events occurred in 57 patients.

A total of 76% of the patients were treated with DMTs. The most commonly prescribed DMTs were interferon beta (40.63%), natalizumab (8.48%), and fingolimod (6.40%). Seventy-eight percent of those who received DMTs started treatment before age 18. Twenty-seven percent received high-efficacy DMTs.

The analysis showed associations between disability and older age at onset [exp(beta), 1.09; 95% confidence interval, 1.03-1.16], maximum EDSS score during the first year of disease [exp(beta), 1.25; 95% CI, 1.13-1.36], or first-year pyramidal symptoms [exp(beta), 1.34; 95% CI, 1.13-1.58], visual symptoms [exp(beta), 1.28; 95% CI, 1.10-1.48], or cerebellum symptoms [exp(beta), 1.17; 95% CI, 1.00-1.39]. A greater amount of time on high-efficacy DMTs was associated with a lower probability of disability [exp(beta), 0.96; 95% CI, 0.93-0.99].

A complete recovery from the first relapse was associated with a lower probability of relapse, though this association did not reach statistical significance [exp(beta), 0.83; 95% CI, 0.68-1.03].

The secondary analyses found that the only predictor of 6-month EDSS worsening [exp(beta), 1.32; 95% CI, 1.21-1.45] was having a maximum EDSS score in the first year. Sensitivity analyses of complete and incomplete recovery from relapses found that a higher MSSS was associated incomplete recovery [exp(beta), 1.16; 95% CI, 1.02-1.32], and confirmed the primary finding that recovery from first relapse was associated with a lower probability of disability [exp(beta), 0.78; 95% CI, 0.63-0.96].

Among patients with MRI data, a new MRI lesion in year 1 was associated with a lower future MSSS score [exp(beta), 0.81; 95% CI, 0.66-0.99].

The study was funded by the National Health and Medical Research Council of Australia. The study authors disclosed ties with a wide range of pharmaceutical companies, including Biogen and Novartis. Dr. Cree has consulted for Biogen, Novartis, and other pharmaceutical companies.

Near-infrared light delivered to the brain using a specially designed helmet appears to improve memory, motor function, and processing skills in cognitively healthy older adults, in new findings that suggest potential benefit in patients with dementia.

Studies in animals and people have shown “many positive effects” with near-infrared transcranial photobiomodulation therapy (PBM-T), study investigator Paul Chazot, PhD, department of biosciences, Durham University, United Kingdom, told this news organization.

For example, PBM-T has been shown to increase blood circulation (which keeps the brain well oxygenated), boost mitochondria function in neurons, protect neurons from oxidative stress, and help maintain neuronal connectivity, Dr. Chazot explained.

PBM-T has also been shown to reduce amyloid and phosphorylated tau load, pathological signs of Alzheimer’s disease.

“All these in combination improve memory performance and mobility,” Dr. Chazot said.

The study was published online October 18 in Photobiomodulation, Photomedicine and Laser Surgery. 
 

Promising early data

In the study, 14 healthy adults, aged 45 to 70 years, received 6 minutes of transcranial PBM-T twice daily at a wavelength of 1,068 nanometers over 4 weeks. PBM-T was delivered via a helmet that comprised 14 air-cooled light emitting diode panel arrays. A control group of 13 adults used a sham PBM-T helmet.

Before and after active and sham treatment, all participants completed the automated neuropsychological assessment metrics (ANAM) – a computer-based tool designed to detect speed and accuracy of attention, memory, and thinking ability.

According to the research team, compared with sham PBM-T, those receiving active PBM-T showed significant improvement in motor function (finger tapping), working memory, delayed memory, and brain processing speed, the research team reports. No adverse effects were reported.

“This study complements our other recent studies, which showed improvement in memory performance with no obvious side effects,” said Dr. Chazot.

“While this is a pilot study and more research is needed, there are promising indications that therapy involving infrared light might also be beneficial for people living with dementia, and this is worth exploring,” Dr. Chazot added in a news release.

The PBM-T helmet was devised by first author Gordon Dougal, MBChB, of Maculume in the U.K., and a general practitioner based in Durham.

A recent study by Mr. Dougal, Dr. Chazot, and collaborators in the United States provides early evidence that PBM-T can improve memory in adults with dementia.

In that study, 39 patients received 6 minutes of PBM-T twice a day for 8 weeks, alongside a control group of 17 patients who received sham PBM-T.

After 8 weeks, there was about a 20% improvement in Mini-Mental State Exam (MMSE) scores in the active PBM-T group compared with roughly a 6% improvement in the control group, the researchers report in the journal Cureus.
 

More research needed

Reached for comment, Rebecca Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said using light to stimulate the brain is “an emerging technology.”

“However, this is a very small study in healthy volunteers, therefore we don’t know from this work alone if this approach would work as an intervention or reduce [the] risk of cognitive decline,” Dr. Edelmayer told this news organization.

“That being said, we’re starting to see companies looking at similar, noninvasive methods of stimulating the brain. For example, brain stimulation devices have been applied to other neurodegenerative diseases like Parkinson’s to try to prevent degeneration of brain cells,” Dr. Edelmayer noted. 

She said more research is needed to understand how photobiomodulation might be used as a therapy or prevention for cognitive decline and dementia.

“Specifically, we need to understand what parts of the brain need to be targeted and at what point(s) in the disease course this treatment would be most impactful. If proven to be effective, this could possibly be part of an approach that’s combined with other treatments, like drugs and lifestyle interventions,” said Dr. Edelmayer.

The Alzheimer’s Association is funding a number of projects looking at noninvasive treatments for Alzheimer’s disease, including two clinical trials looking at deep brain stimulation and photobiomodulation.

Maculume provided funding for the study. Mr. Dougal is a majority shareholder in the company, which manufactures the helmet device used in the study. Dr. Chazot, study co-authors, and Dr. Edelmayer have disclosed no relevant financial relationships.

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

Near-infrared light delivered to the brain using a specially designed helmet appears to improve memory, motor function, and processing skills in cognitively healthy older adults, in new findings that suggest potential benefit in patients with dementia.

Studies in animals and people have shown “many positive effects” with near-infrared transcranial photobiomodulation therapy (PBM-T), study investigator Paul Chazot, PhD, department of biosciences, Durham University, United Kingdom, told this news organization.

For example, PBM-T has been shown to increase blood circulation (which keeps the brain well oxygenated), boost mitochondria function in neurons, protect neurons from oxidative stress, and help maintain neuronal connectivity, Dr. Chazot explained.

PBM-T has also been shown to reduce amyloid and phosphorylated tau load, pathological signs of Alzheimer’s disease.

“All these in combination improve memory performance and mobility,” Dr. Chazot said.

The study was published online October 18 in Photobiomodulation, Photomedicine and Laser Surgery. 
 

Promising early data

In the study, 14 healthy adults, aged 45 to 70 years, received 6 minutes of transcranial PBM-T twice daily at a wavelength of 1,068 nanometers over 4 weeks. PBM-T was delivered via a helmet that comprised 14 air-cooled light emitting diode panel arrays. A control group of 13 adults used a sham PBM-T helmet.

Before and after active and sham treatment, all participants completed the automated neuropsychological assessment metrics (ANAM) – a computer-based tool designed to detect speed and accuracy of attention, memory, and thinking ability.

According to the research team, compared with sham PBM-T, those receiving active PBM-T showed significant improvement in motor function (finger tapping), working memory, delayed memory, and brain processing speed, the research team reports. No adverse effects were reported.

“This study complements our other recent studies, which showed improvement in memory performance with no obvious side effects,” said Dr. Chazot.

“While this is a pilot study and more research is needed, there are promising indications that therapy involving infrared light might also be beneficial for people living with dementia, and this is worth exploring,” Dr. Chazot added in a news release.

The PBM-T helmet was devised by first author Gordon Dougal, MBChB, of Maculume in the U.K., and a general practitioner based in Durham.

A recent study by Mr. Dougal, Dr. Chazot, and collaborators in the United States provides early evidence that PBM-T can improve memory in adults with dementia.

In that study, 39 patients received 6 minutes of PBM-T twice a day for 8 weeks, alongside a control group of 17 patients who received sham PBM-T.

After 8 weeks, there was about a 20% improvement in Mini-Mental State Exam (MMSE) scores in the active PBM-T group compared with roughly a 6% improvement in the control group, the researchers report in the journal Cureus.
 

More research needed

Reached for comment, Rebecca Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said using light to stimulate the brain is “an emerging technology.”

“However, this is a very small study in healthy volunteers, therefore we don’t know from this work alone if this approach would work as an intervention or reduce [the] risk of cognitive decline,” Dr. Edelmayer told this news organization.

“That being said, we’re starting to see companies looking at similar, noninvasive methods of stimulating the brain. For example, brain stimulation devices have been applied to other neurodegenerative diseases like Parkinson’s to try to prevent degeneration of brain cells,” Dr. Edelmayer noted. 

She said more research is needed to understand how photobiomodulation might be used as a therapy or prevention for cognitive decline and dementia.

“Specifically, we need to understand what parts of the brain need to be targeted and at what point(s) in the disease course this treatment would be most impactful. If proven to be effective, this could possibly be part of an approach that’s combined with other treatments, like drugs and lifestyle interventions,” said Dr. Edelmayer.

The Alzheimer’s Association is funding a number of projects looking at noninvasive treatments for Alzheimer’s disease, including two clinical trials looking at deep brain stimulation and photobiomodulation.

Maculume provided funding for the study. Mr. Dougal is a majority shareholder in the company, which manufactures the helmet device used in the study. Dr. Chazot, study co-authors, and Dr. Edelmayer have disclosed no relevant financial relationships.

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

Near-infrared light delivered to the brain using a specially designed helmet appears to improve memory, motor function, and processing skills in cognitively healthy older adults, in new findings that suggest potential benefit in patients with dementia.

Studies in animals and people have shown “many positive effects” with near-infrared transcranial photobiomodulation therapy (PBM-T), study investigator Paul Chazot, PhD, department of biosciences, Durham University, United Kingdom, told this news organization.

For example, PBM-T has been shown to increase blood circulation (which keeps the brain well oxygenated), boost mitochondria function in neurons, protect neurons from oxidative stress, and help maintain neuronal connectivity, Dr. Chazot explained.

PBM-T has also been shown to reduce amyloid and phosphorylated tau load, pathological signs of Alzheimer’s disease.

“All these in combination improve memory performance and mobility,” Dr. Chazot said.

The study was published online October 18 in Photobiomodulation, Photomedicine and Laser Surgery. 
 

Promising early data

In the study, 14 healthy adults, aged 45 to 70 years, received 6 minutes of transcranial PBM-T twice daily at a wavelength of 1,068 nanometers over 4 weeks. PBM-T was delivered via a helmet that comprised 14 air-cooled light emitting diode panel arrays. A control group of 13 adults used a sham PBM-T helmet.

Before and after active and sham treatment, all participants completed the automated neuropsychological assessment metrics (ANAM) – a computer-based tool designed to detect speed and accuracy of attention, memory, and thinking ability.

According to the research team, compared with sham PBM-T, those receiving active PBM-T showed significant improvement in motor function (finger tapping), working memory, delayed memory, and brain processing speed, the research team reports. No adverse effects were reported.

“This study complements our other recent studies, which showed improvement in memory performance with no obvious side effects,” said Dr. Chazot.

“While this is a pilot study and more research is needed, there are promising indications that therapy involving infrared light might also be beneficial for people living with dementia, and this is worth exploring,” Dr. Chazot added in a news release.

The PBM-T helmet was devised by first author Gordon Dougal, MBChB, of Maculume in the U.K., and a general practitioner based in Durham.

A recent study by Mr. Dougal, Dr. Chazot, and collaborators in the United States provides early evidence that PBM-T can improve memory in adults with dementia.

In that study, 39 patients received 6 minutes of PBM-T twice a day for 8 weeks, alongside a control group of 17 patients who received sham PBM-T.

After 8 weeks, there was about a 20% improvement in Mini-Mental State Exam (MMSE) scores in the active PBM-T group compared with roughly a 6% improvement in the control group, the researchers report in the journal Cureus.
 

More research needed

Reached for comment, Rebecca Edelmayer, PhD, Alzheimer’s Association senior director of scientific engagement, said using light to stimulate the brain is “an emerging technology.”

“However, this is a very small study in healthy volunteers, therefore we don’t know from this work alone if this approach would work as an intervention or reduce [the] risk of cognitive decline,” Dr. Edelmayer told this news organization.

“That being said, we’re starting to see companies looking at similar, noninvasive methods of stimulating the brain. For example, brain stimulation devices have been applied to other neurodegenerative diseases like Parkinson’s to try to prevent degeneration of brain cells,” Dr. Edelmayer noted. 

She said more research is needed to understand how photobiomodulation might be used as a therapy or prevention for cognitive decline and dementia.

“Specifically, we need to understand what parts of the brain need to be targeted and at what point(s) in the disease course this treatment would be most impactful. If proven to be effective, this could possibly be part of an approach that’s combined with other treatments, like drugs and lifestyle interventions,” said Dr. Edelmayer.

The Alzheimer’s Association is funding a number of projects looking at noninvasive treatments for Alzheimer’s disease, including two clinical trials looking at deep brain stimulation and photobiomodulation.

Maculume provided funding for the study. Mr. Dougal is a majority shareholder in the company, which manufactures the helmet device used in the study. Dr. Chazot, study co-authors, and Dr. Edelmayer have disclosed no relevant financial relationships.

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

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

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

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

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

Antithrombotic therapy in clinically stable, nonhospitalized COVID-19 patients does not offer protection against adverse cardiovascular or pulmonary events, new randomized clinical trial results suggest.

Bruce Jancin/MDedge News

Antithrombotic therapy has proven useful in acutely ill inpatients with COVID-19, but in this study, treatment with aspirin or apixaban (Eliquis) did not reduce the rate of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary causes in patients ill with COVID-19 but who were not hospitalized.

“Among symptomatic, clinically stable outpatients with COVID-19, treatment with aspirin or apixaban compared with placebo did not reduce the rate of a composite clinical outcome,” the authors conclude. “However, the study was terminated after enrollment of 9% of participants because of a primary event rate lower than anticipated.”

The study, which was led by Jean M. Connors, MD, Brigham and Women’s Hospital, Boston, was published online October 11 in JAMA.

The ACTIV-4B Outpatient Thrombosis Prevention Trial was a randomized, adaptive, double-blind, placebo-controlled trial that sought to compare anticoagulant and antiplatelet therapy among 7,000 symptomatic but clinically stable outpatients with COVID-19.

The trial was conducted at 52 sites in the U.S. between Sept. 2020 and June 2021, with final follow-up this past August 5, and involved minimal face-to-face interactions with study participants.

Patients were randomized in a 1:1:1:1 ratio to aspirin (81 mg orally once daily; n = 164 patients), prophylactic-dose apixaban (2.5 mg orally twice daily; n = 165), therapeutic-dose apixaban (5 mg orally twice daily; n = 164), or placebo (n = 164) for 45 days.

The primary endpoint was a composite of all-cause mortality, symptomatic venous or arterial thromboembolism, myocardial infarction, stroke, or hospitalization for cardiovascular or pulmonary cause.

The trial was terminated early this past June by the independent data monitoring committee because of lower than anticipated event rates. At the time, just 657 symptomatic outpatients with COVID-19 had been enrolled.

The median age of the study participants was 54 years (Interquartile Range [IQR] 46-59); 59% were women.

The median time from diagnosis to randomization was 7 days, and the median time from randomization to initiation of study medications was 3 days.

The trial’s primary efficacy and safety analyses were restricted to patients who received at least one dose of trial medication, for a final number of 558 patients.

Among these patients, the primary endpoint occurred in 1 patient (0.7%) in the aspirin group, 1 patient (0.7%) in the 2.5 mg apixaban group, 2 patients (1.4%) in the 5-mg apixaban group, and 1 patient (0.7%) in the placebo group.

The researchers found that the absolute risk reductions compared with placebo for the primary outcome were 0.0% (95% confidence interval not calculable) in the aspirin group, 0.7% (95% confidence interval, -2.1% to 4.1%) in the prophylactic-dose apixaban group, and 1.4% (95% CI, -1.5% to 5%) in the therapeutic-dose apixaban group.

No major bleeding events were reported.

The absolute risk differences compared with placebo for clinically relevant nonmajor bleeding events were 2% (95% CI, -2.7% to 6.8%) in the aspirin group, 4.5% (95% CI, -0.7% to 10.2%) in the prophylactic-dose apixaban group, and 6.9% (95% CI, 1.4% to 12.9%) in the therapeutic-dose apixaban group.

Safety and efficacy results were similar in all randomly assigned patients.

The researchers speculated that a combination of two demographic shifts over time may have led to the lower than anticipated rate of events in ACTIV-4B.

“First, the threshold for hospital admission has markedly declined since the beginning of the pandemic, such that hospitalization is no longer limited almost exclusively to those with severe pulmonary distress likely to require mechanical ventilation,” they write. “As a result, the severity of illness among individuals with COVID-19 and destined for outpatient care has declined.”

“Second, at least within the U.S., where the trial was conducted, individuals currently being infected with SARS-CoV-2 tend to be younger and have fewer comorbidities when compared with individuals with incident infection at the onset of the pandemic,” they add.

Further, COVID-19 testing was quite limited early in the pandemic, they note, “and it is possible that the anticipated event rates based on data from registries available at that time were overestimated because the denominator (that is, the number of infected individuals overall) was essentially unknown.”
 

Robust evidence

“The ACTIV-4B trial is the first randomized trial to generate robust evidence about the effects of antithrombotic therapy in outpatients with COVID-19,” Otavio Berwanger, MD, PhD, director of the Academic Research Organization, Hospital Israelita Albert Einstein, Sao Paulo-SP, Brazil, told this news organization.

“It should be noted that this was a well-designed trial with low risk of bias. On the other hand, the main limitation is the low number of events and, consequently, the limited statistical power,” said Dr. Berwanger, who wrote an accompanying editorial.

The ACTIV-4B trial has immediate implications for clinical practice, he added.

“In this sense, considering the neutral results for major cardiopulmonary outcomes, the use of aspirin or apixaban for the management of outpatients with COVID-19 should not be recommended.”

ACTIV-4B also provides useful information for the steering committees of other ongoing trials of antithrombotic therapy for patients with COVID-19 who are not hospitalized, Dr. Berwanger added.

“In this sense, probably issues like statistical power, outcome choices, recruitment feasibility, and even futility would need to be revisited. And finally, lessons learned from the implementation of an innovative, pragmatic, and decentralized trial design represent an important legacy for future trials in cardiovascular diseases and other common conditions,” he said.

The study was funded by the National Institutes of Health, and the National Heart, Lung, and Blood Institute. Dr. Connors reports financial relationships with Bristol-Myers Squibb, Pfizer, Abbott, Alnylam, Takeda, Roche, and Sanofi. Dr. Berwanger reports financial relationships with AstraZeneca, Amgen, Servier, Bristol-Myers Squibb, Bayer, Novartis, Pfizer, and Boehringer Ingelheim.

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

Motor imagery (MI) is a useful tool in the management of multiple sclerosis (MS), with the potential to improve balance, walking, and even cognitive function and mental health. It’s a technique that many think of as the realm of professional athletes, who use it to help mentally prepare for physical activity. But the underlying mechanism has broad applicability, even in patients with MS who have disability.

The method recruits and employs motor-related areas within the brain, which suggests that it has functional equivalence to carrying out the rehearsed movement. The mental chronometry is also similar between imagined and executed actions, said Barbara Seebacher, PhD, who discussed MI during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

MI involves mentally rehearsing movements, and so requires working memory. The patient must also have the fundamental ability to carry out the action, so it isn’t much use having nonambulatory patients imagine themselves walking. “The mental representations need to be available,” said Dr. Seebacher, a researcher at Medical University of Innsbruck in Austria.

During MI, individuals may imagine themselves from a first- or third-person view. The experience may be visual, as in picturing oneself moving, or kinesthetic, as in imagining the feeling of movement. There can be implicit components, such as imagining a projection of the speed and distance of an approaching car, and explicit, such as imagining the personal movement of walking across the street.

The use of MI in MS rehabilitation is a relatively new development, with no reports before 2010. One early, uncontrolled study found improvements in fatigue and quality of life when MI was combined with physical practice in 20 patients. Another study published in 2012 found that MS patients had worse MI accuracy and temporal organization than that of healthy controls, and that MI accuracy was associated with cognitive impairment.

A study in 2012 used visual and rhythmic cues combined with MI, and compared results when those cues were present or absent during MI. The cues produced much better results. Dr. Seebacher’s group has used rhythmic, auditory-cued MI of walking in people with MS. Approaches included music cueing, music and verbal cueing, metronome and verbal cueing, and no cue MI. “We found significant effects after all of these approaches, but the greatest effects were shown after music and verbally-cued MI practice,” said Dr. Seebacher.

MI ability appears to be impaired by longer MS disease duration, more severe disability, depression and anxiety, and cognitive fatigue. “All of this contributes to timing deficits in performing mental movements and to deficits in the spatial organization of imagined movements,” said Dr. Seebacher.

In contrast, studies have shown that MI training improves dynamic balance, walking, perceived walking ability, balance, confidence, cognition, fatigue, anxiety and depression, quality of life, and health-related quality of life.

Rehabilitation specialists can help patients achieve success with MI by letting them select their preferred perspective, first or third person, at least during initial sessions. Patients can also be given the choice to use a more dexterous, more often-used body part, at least in initial MI sessions. External rhythmic, audio, or visual cuing can be offered.

Dr. Seebacher has developed an initial framework for helping patients to improve their MI ability. This includes assessing rhythmicity of single imagined movements to help ensure that MI and movements are functionally equivalent. Another step is to incorporate movements that are meaningful to the patients, to help ensure that they are emotionally engaged with the exercise. Research conducted primarily in stroke patients has shown that embedding physical practice into MI, or adding physical movement to MI, can enhance sensory feedback.

Motor learning principles from neurorehabilitation also apply to MI, such as beginning with simple tasks and progressing to more complex tasks, as well as use of blocked practice before turning to random practice. “All this should help our patients to perform MI more easily and to gain a greater benefit,” said Dr. Seebacher.

The potential of MI piqued the interest of comoderator Hanneke Hulst, PhD, assistant professor of neurology at Amsterdam University Medical Center, during the Q&A session. “It’s actually very intriguing and interesting,” she said, and then asked Dr. Seebacher how difficult MI is to implement in a rehabilitation program, especially for someone who isn’t a rehabilitation specialist.

Dr. Seebacher responded that it can be difficult, especially because patients and therapists usually aren’t familiar with MI. “Whenever I explain MI to patients, I compare it with athletes, because everybody knows that athletes use mental training, together with their physical training. And this is something patients can identify themselves with,” said Dr. Seebacher. It’s also vital that the patient has preserved cognitive function, and is open to a new therapeutic approach. “If somebody just wants to act the same way that they did all the time, it may not be useful for these patients,” said Dr. Seebacher.

MI is also useful for patients who have difficulty with physical training, for example following relapses, or for those who are at greater risk of falling.

Dr. Seebacher has no relevant financial disclosures. Dr. Hulst has consulted with or served on the scientific advisory boards of Biogen, Celgene, Genzyme, Merck, and Roche.

Motor imagery (MI) is a useful tool in the management of multiple sclerosis (MS), with the potential to improve balance, walking, and even cognitive function and mental health. It’s a technique that many think of as the realm of professional athletes, who use it to help mentally prepare for physical activity. But the underlying mechanism has broad applicability, even in patients with MS who have disability.

The method recruits and employs motor-related areas within the brain, which suggests that it has functional equivalence to carrying out the rehearsed movement. The mental chronometry is also similar between imagined and executed actions, said Barbara Seebacher, PhD, who discussed MI during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

MI involves mentally rehearsing movements, and so requires working memory. The patient must also have the fundamental ability to carry out the action, so it isn’t much use having nonambulatory patients imagine themselves walking. “The mental representations need to be available,” said Dr. Seebacher, a researcher at Medical University of Innsbruck in Austria.

During MI, individuals may imagine themselves from a first- or third-person view. The experience may be visual, as in picturing oneself moving, or kinesthetic, as in imagining the feeling of movement. There can be implicit components, such as imagining a projection of the speed and distance of an approaching car, and explicit, such as imagining the personal movement of walking across the street.

The use of MI in MS rehabilitation is a relatively new development, with no reports before 2010. One early, uncontrolled study found improvements in fatigue and quality of life when MI was combined with physical practice in 20 patients. Another study published in 2012 found that MS patients had worse MI accuracy and temporal organization than that of healthy controls, and that MI accuracy was associated with cognitive impairment.

A study in 2012 used visual and rhythmic cues combined with MI, and compared results when those cues were present or absent during MI. The cues produced much better results. Dr. Seebacher’s group has used rhythmic, auditory-cued MI of walking in people with MS. Approaches included music cueing, music and verbal cueing, metronome and verbal cueing, and no cue MI. “We found significant effects after all of these approaches, but the greatest effects were shown after music and verbally-cued MI practice,” said Dr. Seebacher.

MI ability appears to be impaired by longer MS disease duration, more severe disability, depression and anxiety, and cognitive fatigue. “All of this contributes to timing deficits in performing mental movements and to deficits in the spatial organization of imagined movements,” said Dr. Seebacher.

In contrast, studies have shown that MI training improves dynamic balance, walking, perceived walking ability, balance, confidence, cognition, fatigue, anxiety and depression, quality of life, and health-related quality of life.

Rehabilitation specialists can help patients achieve success with MI by letting them select their preferred perspective, first or third person, at least during initial sessions. Patients can also be given the choice to use a more dexterous, more often-used body part, at least in initial MI sessions. External rhythmic, audio, or visual cuing can be offered.

Dr. Seebacher has developed an initial framework for helping patients to improve their MI ability. This includes assessing rhythmicity of single imagined movements to help ensure that MI and movements are functionally equivalent. Another step is to incorporate movements that are meaningful to the patients, to help ensure that they are emotionally engaged with the exercise. Research conducted primarily in stroke patients has shown that embedding physical practice into MI, or adding physical movement to MI, can enhance sensory feedback.

Motor learning principles from neurorehabilitation also apply to MI, such as beginning with simple tasks and progressing to more complex tasks, as well as use of blocked practice before turning to random practice. “All this should help our patients to perform MI more easily and to gain a greater benefit,” said Dr. Seebacher.

The potential of MI piqued the interest of comoderator Hanneke Hulst, PhD, assistant professor of neurology at Amsterdam University Medical Center, during the Q&A session. “It’s actually very intriguing and interesting,” she said, and then asked Dr. Seebacher how difficult MI is to implement in a rehabilitation program, especially for someone who isn’t a rehabilitation specialist.

Dr. Seebacher responded that it can be difficult, especially because patients and therapists usually aren’t familiar with MI. “Whenever I explain MI to patients, I compare it with athletes, because everybody knows that athletes use mental training, together with their physical training. And this is something patients can identify themselves with,” said Dr. Seebacher. It’s also vital that the patient has preserved cognitive function, and is open to a new therapeutic approach. “If somebody just wants to act the same way that they did all the time, it may not be useful for these patients,” said Dr. Seebacher.

MI is also useful for patients who have difficulty with physical training, for example following relapses, or for those who are at greater risk of falling.

Dr. Seebacher has no relevant financial disclosures. Dr. Hulst has consulted with or served on the scientific advisory boards of Biogen, Celgene, Genzyme, Merck, and Roche.

Motor imagery (MI) is a useful tool in the management of multiple sclerosis (MS), with the potential to improve balance, walking, and even cognitive function and mental health. It’s a technique that many think of as the realm of professional athletes, who use it to help mentally prepare for physical activity. But the underlying mechanism has broad applicability, even in patients with MS who have disability.

The method recruits and employs motor-related areas within the brain, which suggests that it has functional equivalence to carrying out the rehearsed movement. The mental chronometry is also similar between imagined and executed actions, said Barbara Seebacher, PhD, who discussed MI during a presentation at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

MI involves mentally rehearsing movements, and so requires working memory. The patient must also have the fundamental ability to carry out the action, so it isn’t much use having nonambulatory patients imagine themselves walking. “The mental representations need to be available,” said Dr. Seebacher, a researcher at Medical University of Innsbruck in Austria.

During MI, individuals may imagine themselves from a first- or third-person view. The experience may be visual, as in picturing oneself moving, or kinesthetic, as in imagining the feeling of movement. There can be implicit components, such as imagining a projection of the speed and distance of an approaching car, and explicit, such as imagining the personal movement of walking across the street.

The use of MI in MS rehabilitation is a relatively new development, with no reports before 2010. One early, uncontrolled study found improvements in fatigue and quality of life when MI was combined with physical practice in 20 patients. Another study published in 2012 found that MS patients had worse MI accuracy and temporal organization than that of healthy controls, and that MI accuracy was associated with cognitive impairment.

A study in 2012 used visual and rhythmic cues combined with MI, and compared results when those cues were present or absent during MI. The cues produced much better results. Dr. Seebacher’s group has used rhythmic, auditory-cued MI of walking in people with MS. Approaches included music cueing, music and verbal cueing, metronome and verbal cueing, and no cue MI. “We found significant effects after all of these approaches, but the greatest effects were shown after music and verbally-cued MI practice,” said Dr. Seebacher.

MI ability appears to be impaired by longer MS disease duration, more severe disability, depression and anxiety, and cognitive fatigue. “All of this contributes to timing deficits in performing mental movements and to deficits in the spatial organization of imagined movements,” said Dr. Seebacher.

In contrast, studies have shown that MI training improves dynamic balance, walking, perceived walking ability, balance, confidence, cognition, fatigue, anxiety and depression, quality of life, and health-related quality of life.

Rehabilitation specialists can help patients achieve success with MI by letting them select their preferred perspective, first or third person, at least during initial sessions. Patients can also be given the choice to use a more dexterous, more often-used body part, at least in initial MI sessions. External rhythmic, audio, or visual cuing can be offered.

Dr. Seebacher has developed an initial framework for helping patients to improve their MI ability. This includes assessing rhythmicity of single imagined movements to help ensure that MI and movements are functionally equivalent. Another step is to incorporate movements that are meaningful to the patients, to help ensure that they are emotionally engaged with the exercise. Research conducted primarily in stroke patients has shown that embedding physical practice into MI, or adding physical movement to MI, can enhance sensory feedback.

Motor learning principles from neurorehabilitation also apply to MI, such as beginning with simple tasks and progressing to more complex tasks, as well as use of blocked practice before turning to random practice. “All this should help our patients to perform MI more easily and to gain a greater benefit,” said Dr. Seebacher.

The potential of MI piqued the interest of comoderator Hanneke Hulst, PhD, assistant professor of neurology at Amsterdam University Medical Center, during the Q&A session. “It’s actually very intriguing and interesting,” she said, and then asked Dr. Seebacher how difficult MI is to implement in a rehabilitation program, especially for someone who isn’t a rehabilitation specialist.

Dr. Seebacher responded that it can be difficult, especially because patients and therapists usually aren’t familiar with MI. “Whenever I explain MI to patients, I compare it with athletes, because everybody knows that athletes use mental training, together with their physical training. And this is something patients can identify themselves with,” said Dr. Seebacher. It’s also vital that the patient has preserved cognitive function, and is open to a new therapeutic approach. “If somebody just wants to act the same way that they did all the time, it may not be useful for these patients,” said Dr. Seebacher.

MI is also useful for patients who have difficulty with physical training, for example following relapses, or for those who are at greater risk of falling.

Dr. Seebacher has no relevant financial disclosures. Dr. Hulst has consulted with or served on the scientific advisory boards of Biogen, Celgene, Genzyme, Merck, and Roche.

Though once regarded with suspicion, exercise as a therapy for multiple sclerosis (MS) has gained traction in recent years, and has the potential to counter the physical effects often seen among patients, as well as reduce risk of progression.

That was the key message of a talk given by Ulrik Dalgas, PhD, professor of exercise biology at Aarhus University in Denmark, who spoke at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Rethinking the role of exercise

It used to be thought that exercise could worsen disease, but case studies in the 1960s suggested some beneficial effects. The first interventional studies were published in the 1990s. A 2008 special issue of Multiple Sclerosis Journal declared exercise safe for people with MS. Research has continued to evolve, “and now we are actually at a stage where some of us have started to believe that exercise is a medicine in multiple sclerosis,” said Dr. Dalgas, who outlined that view in a 2019 review paper.

In the early phase of MS, before the onset of a significant decline in brain volume or increase in disability, there are already measurable physical deficits. Dr. Dalgas showed data from an unpublished study from his group, which looked at 48 patients who had been diagnosed in the previous 2 years, at an average 10 months after diagnosis. “Already at this very early stage of the disease, we can actually observe impairments or deficits in walking, different walking outcome measures here between 10 and up to more than 30%, depending on the walking outcome,” said Dr. Dalgas. Similar deficits appeared in physical activity and maximum rate of oxygen consumption (VO₂ max).

Animal studies suggest that exercise could improve matters at this stage. In a model of experimental autoimmune encephalomyelitis, animals allowed the opportunity to exercise had lower levels of clinical disability throughout the model disease course. That has led some to examine a “prehabilitation” approach to early MS – a term borrowed from orthopedics. “We try to prevent rather than to treat symptoms, or build reserve capacity rather than restore capacity,” said Dr. Dalgas.

Some work in this area has been done in human patients, but a review found that none of more than 70 published studies looked at patients within 5 years of onset. “That left kind of an unstudied early phase,” said Dr. Dalgas.

In the mid-phase of MS, when brain volume loss increases and mobility and other problems increase, exercise has proved to counteract some of these issues. “What we are now trying to do is figure out what are the best exercise modalities for treating different symptoms,” said Dr. Dalgas.

Resistance and aerobic training have predictable, positive effects on strength and VO₂ max, but one study showed that the two modes of exercise had similar positive impacts on short and long walks, as well as fatigue, despite the fact that they have very different physiological effects.

Other studies have looked at the impact of exercise on the diseases itself. One recent study examined aerobic exercise versus a wait-list group. Gray matter volume remained stable in the exercise group, but dropped in the wait-list group, suggesting a possible protective effect .

In the later, more severe phase of MS, more specialized equipment is needed to ensure safety during exercise. A pilot study by Dr. Dalgas’ group in individuals with Expanded Disability Status Scores (EDSS) scores between 6.5 and 8 found that upper body exercise improved VO₂ peak score in five out of six patients. “Even at this later stage of the disease, it seems that people can still have important improvements in health and performance markers,” said Dr. Dalgas.

A review of numerous studies found that exercise had a positive effect on quality of life, and the gains were not affected by baseline disability, disease duration, or exercise type. The study shows that “it’s never too late to improve your life through exercise,” said Dr. Dalgas.
 

Next steps

Challenges remain for the field. “We still need to figure out how long-term adherence is best secured in these patients, and then we really need to look further into how to provide exercise in the best possible way in severe and elderly patients,” said Dr. Dalgas.

During the Q&A session following the presentation, Dr. Dalgas was asked for advice on how to get a patient with MS started with exercise. “We normally recommend that people should find a physical therapist or sports scientist who has expertise in this field to help with getting started. If you start out wrong you can get into problems, so having the right expertise at hand is a good way to start. Then shortly afterward they will be more independent to do the exercise,” said Dr. Dalgas.

Alan Thompson, MD, who moderated the session, brought up the concept of cognitive reserve in MS, which posits that positive life experience builds up the capacity and efficiency of neural networks, which in turn act as a sort of buffer against later cognitive decline due to aging and illness. “Can you build up your exercises in a way that has a meaningful impact in delaying the onset of confirmed disability or progression?” asked Dr. Thompson, professor of clinical neurology and neurorehabilitation at University College London.

Dr. Dalgas said that there are studies that suggest this may be true, with MS diagnoses occurring later in patients who are physically active. “You can interpret that as some kind of delayed onset of the disease.”

For more information, Dr. Dalgas suggested recently published recommendations for exercise in MS patients.

Dr. Dalgas disclosed ties with Biogen Idec, Merck Serono, Sanofi Aventis, Almirall, Novartis, Bayer Schering, and Sanofi Genzyme. Dr. Thompson has no relevant financial disclosures.

Though once regarded with suspicion, exercise as a therapy for multiple sclerosis (MS) has gained traction in recent years, and has the potential to counter the physical effects often seen among patients, as well as reduce risk of progression.

That was the key message of a talk given by Ulrik Dalgas, PhD, professor of exercise biology at Aarhus University in Denmark, who spoke at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Rethinking the role of exercise

It used to be thought that exercise could worsen disease, but case studies in the 1960s suggested some beneficial effects. The first interventional studies were published in the 1990s. A 2008 special issue of Multiple Sclerosis Journal declared exercise safe for people with MS. Research has continued to evolve, “and now we are actually at a stage where some of us have started to believe that exercise is a medicine in multiple sclerosis,” said Dr. Dalgas, who outlined that view in a 2019 review paper.

In the early phase of MS, before the onset of a significant decline in brain volume or increase in disability, there are already measurable physical deficits. Dr. Dalgas showed data from an unpublished study from his group, which looked at 48 patients who had been diagnosed in the previous 2 years, at an average 10 months after diagnosis. “Already at this very early stage of the disease, we can actually observe impairments or deficits in walking, different walking outcome measures here between 10 and up to more than 30%, depending on the walking outcome,” said Dr. Dalgas. Similar deficits appeared in physical activity and maximum rate of oxygen consumption (VO₂ max).

Animal studies suggest that exercise could improve matters at this stage. In a model of experimental autoimmune encephalomyelitis, animals allowed the opportunity to exercise had lower levels of clinical disability throughout the model disease course. That has led some to examine a “prehabilitation” approach to early MS – a term borrowed from orthopedics. “We try to prevent rather than to treat symptoms, or build reserve capacity rather than restore capacity,” said Dr. Dalgas.

Some work in this area has been done in human patients, but a review found that none of more than 70 published studies looked at patients within 5 years of onset. “That left kind of an unstudied early phase,” said Dr. Dalgas.

In the mid-phase of MS, when brain volume loss increases and mobility and other problems increase, exercise has proved to counteract some of these issues. “What we are now trying to do is figure out what are the best exercise modalities for treating different symptoms,” said Dr. Dalgas.

Resistance and aerobic training have predictable, positive effects on strength and VO₂ max, but one study showed that the two modes of exercise had similar positive impacts on short and long walks, as well as fatigue, despite the fact that they have very different physiological effects.

Other studies have looked at the impact of exercise on the diseases itself. One recent study examined aerobic exercise versus a wait-list group. Gray matter volume remained stable in the exercise group, but dropped in the wait-list group, suggesting a possible protective effect .

In the later, more severe phase of MS, more specialized equipment is needed to ensure safety during exercise. A pilot study by Dr. Dalgas’ group in individuals with Expanded Disability Status Scores (EDSS) scores between 6.5 and 8 found that upper body exercise improved VO₂ peak score in five out of six patients. “Even at this later stage of the disease, it seems that people can still have important improvements in health and performance markers,” said Dr. Dalgas.

A review of numerous studies found that exercise had a positive effect on quality of life, and the gains were not affected by baseline disability, disease duration, or exercise type. The study shows that “it’s never too late to improve your life through exercise,” said Dr. Dalgas.
 

Next steps

Challenges remain for the field. “We still need to figure out how long-term adherence is best secured in these patients, and then we really need to look further into how to provide exercise in the best possible way in severe and elderly patients,” said Dr. Dalgas.

During the Q&A session following the presentation, Dr. Dalgas was asked for advice on how to get a patient with MS started with exercise. “We normally recommend that people should find a physical therapist or sports scientist who has expertise in this field to help with getting started. If you start out wrong you can get into problems, so having the right expertise at hand is a good way to start. Then shortly afterward they will be more independent to do the exercise,” said Dr. Dalgas.

Alan Thompson, MD, who moderated the session, brought up the concept of cognitive reserve in MS, which posits that positive life experience builds up the capacity and efficiency of neural networks, which in turn act as a sort of buffer against later cognitive decline due to aging and illness. “Can you build up your exercises in a way that has a meaningful impact in delaying the onset of confirmed disability or progression?” asked Dr. Thompson, professor of clinical neurology and neurorehabilitation at University College London.

Dr. Dalgas said that there are studies that suggest this may be true, with MS diagnoses occurring later in patients who are physically active. “You can interpret that as some kind of delayed onset of the disease.”

For more information, Dr. Dalgas suggested recently published recommendations for exercise in MS patients.

Dr. Dalgas disclosed ties with Biogen Idec, Merck Serono, Sanofi Aventis, Almirall, Novartis, Bayer Schering, and Sanofi Genzyme. Dr. Thompson has no relevant financial disclosures.

Though once regarded with suspicion, exercise as a therapy for multiple sclerosis (MS) has gained traction in recent years, and has the potential to counter the physical effects often seen among patients, as well as reduce risk of progression.

That was the key message of a talk given by Ulrik Dalgas, PhD, professor of exercise biology at Aarhus University in Denmark, who spoke at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
 

Rethinking the role of exercise

It used to be thought that exercise could worsen disease, but case studies in the 1960s suggested some beneficial effects. The first interventional studies were published in the 1990s. A 2008 special issue of Multiple Sclerosis Journal declared exercise safe for people with MS. Research has continued to evolve, “and now we are actually at a stage where some of us have started to believe that exercise is a medicine in multiple sclerosis,” said Dr. Dalgas, who outlined that view in a 2019 review paper.

In the early phase of MS, before the onset of a significant decline in brain volume or increase in disability, there are already measurable physical deficits. Dr. Dalgas showed data from an unpublished study from his group, which looked at 48 patients who had been diagnosed in the previous 2 years, at an average 10 months after diagnosis. “Already at this very early stage of the disease, we can actually observe impairments or deficits in walking, different walking outcome measures here between 10 and up to more than 30%, depending on the walking outcome,” said Dr. Dalgas. Similar deficits appeared in physical activity and maximum rate of oxygen consumption (VO₂ max).

Animal studies suggest that exercise could improve matters at this stage. In a model of experimental autoimmune encephalomyelitis, animals allowed the opportunity to exercise had lower levels of clinical disability throughout the model disease course. That has led some to examine a “prehabilitation” approach to early MS – a term borrowed from orthopedics. “We try to prevent rather than to treat symptoms, or build reserve capacity rather than restore capacity,” said Dr. Dalgas.

Some work in this area has been done in human patients, but a review found that none of more than 70 published studies looked at patients within 5 years of onset. “That left kind of an unstudied early phase,” said Dr. Dalgas.

In the mid-phase of MS, when brain volume loss increases and mobility and other problems increase, exercise has proved to counteract some of these issues. “What we are now trying to do is figure out what are the best exercise modalities for treating different symptoms,” said Dr. Dalgas.

Resistance and aerobic training have predictable, positive effects on strength and VO₂ max, but one study showed that the two modes of exercise had similar positive impacts on short and long walks, as well as fatigue, despite the fact that they have very different physiological effects.

Other studies have looked at the impact of exercise on the diseases itself. One recent study examined aerobic exercise versus a wait-list group. Gray matter volume remained stable in the exercise group, but dropped in the wait-list group, suggesting a possible protective effect .

In the later, more severe phase of MS, more specialized equipment is needed to ensure safety during exercise. A pilot study by Dr. Dalgas’ group in individuals with Expanded Disability Status Scores (EDSS) scores between 6.5 and 8 found that upper body exercise improved VO₂ peak score in five out of six patients. “Even at this later stage of the disease, it seems that people can still have important improvements in health and performance markers,” said Dr. Dalgas.

A review of numerous studies found that exercise had a positive effect on quality of life, and the gains were not affected by baseline disability, disease duration, or exercise type. The study shows that “it’s never too late to improve your life through exercise,” said Dr. Dalgas.
 

Next steps

Challenges remain for the field. “We still need to figure out how long-term adherence is best secured in these patients, and then we really need to look further into how to provide exercise in the best possible way in severe and elderly patients,” said Dr. Dalgas.

During the Q&A session following the presentation, Dr. Dalgas was asked for advice on how to get a patient with MS started with exercise. “We normally recommend that people should find a physical therapist or sports scientist who has expertise in this field to help with getting started. If you start out wrong you can get into problems, so having the right expertise at hand is a good way to start. Then shortly afterward they will be more independent to do the exercise,” said Dr. Dalgas.

Alan Thompson, MD, who moderated the session, brought up the concept of cognitive reserve in MS, which posits that positive life experience builds up the capacity and efficiency of neural networks, which in turn act as a sort of buffer against later cognitive decline due to aging and illness. “Can you build up your exercises in a way that has a meaningful impact in delaying the onset of confirmed disability or progression?” asked Dr. Thompson, professor of clinical neurology and neurorehabilitation at University College London.

Dr. Dalgas said that there are studies that suggest this may be true, with MS diagnoses occurring later in patients who are physically active. “You can interpret that as some kind of delayed onset of the disease.”

For more information, Dr. Dalgas suggested recently published recommendations for exercise in MS patients.

Dr. Dalgas disclosed ties with Biogen Idec, Merck Serono, Sanofi Aventis, Almirall, Novartis, Bayer Schering, and Sanofi Genzyme. Dr. Thompson has no relevant financial disclosures.