TBD Meeting (2962-21)

A novel, once-nightly formulation of sodium oxybate is safe and effective for treating both subjective and objective symptoms of narcolepsy, new research suggests. Top-line results from the phase 3 REST-ON trial released earlier this year showed that the agent known as FT218 (Avadel Pharmaceuticals) met all three of its coprimary efficacy endpoints at all three doses assessed (6 g, 7.5 g, and 9 g). Patients receiving the drug showed significantly greater improvements on the Maintenance of Wakefulness Test (MWT), the Clinical Global Impression of Improvement (CGI-I), and mean weekly attacks of cataplexy, compared with those who received placebo.

The new analyses, which focused on key secondary outcomes, showed that all three doses of the novel agent were associated with significant improvements in sleep quality, refreshing nature of sleep, sleep paralysis, disturbed nocturnal sleep, and scores on the Epworth Sleepiness Scale (ESS).

Principal investigator Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, New York, said in a news release that the results represent “the promise of a potential new treatment strategy for physicians and patients.”

“I am particularly impressed by the consistency of results as early as 3 weeks with only a 6-g dose,” he added.

Dr. Thorpy, who is also a professor of neurology at the Albert Einstein College of Medicine, noted that the new formulation will be more convenient for patients. “The advantage of this medication is its once-nightly formulation, so patients don’t need to awaken during the night and can actually have a better night’s sleep,” he said.

Dr. Thorpy presented the study findings at the 2021 annual meeting of the American Academy of Neurology.

FT218 is currently under review by the U.S. Food and Drug Administration, which has set Oct. 15 as the Prescription Drug User Fee Act target date.

Forced awakening

Sodium oxybate was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy and was expanded in 2005 to also treat excessive daytime sleepiness (EDS). That formulation is indicated for twice-nightly administration, with the second dose taken 2.5-4 hours after the first.

“The need for forced awakening to take the second dose ... may result in noncompliance, which may lead to reduced efficacy and/or mistimed doses,” the investigators noted.

FT218 is a modified-release version of sodium oxybate. A single 6-g dose of the investigational agent “has shown bioequivalent exposure to twice-nightly immediate-release [sodium oxybate] given as two 3-g doses,” wrote the researchers.

It also currently has Orphan Drug Designation from the FDA for the treatment of narcolepsy.

The randomized, double-blind, placebo-controlled, multicenter REST-ON study was conducted from November 2016 to March 2020 and included patients 16 years or older who had narcolepsy type 1 or type 2.

Patients received the active treatment (n = 107; mean age, 30.9 years; 64.5% women) or placebo (n = 105; mean age, 31.6 years; 71.4% women) according to a four-period forced uptitration dosing schedule of 4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and 9 g for 5 weeks.

Secondary outcome measures included the ESS, sleep quality/refreshing nature of sleep on a visual analog scale, sleep paralysis and hypnagogic hallucinations on a sleep symptoms diary, disturbed nocturnal sleep on polysomnographic measures, and number of arousals as defined per the American Academy of Sleep Medicine Score Manual.

Reports of adverse events (AEs) were collected from time of informed consent until 7 days after the last dose received.

Improvement across doses

Results showed that, compared with placebo, improvement in disturbed nocturnal sleep from baseline was significantly greater for the active treatment at 6 g at week 3 (mean between-group difference, –11; P < .001), at 7.5 g at week 8 (mean difference, –17.7; P < .001), and at 9 g at week 13 (mean difference, –22.6; P < .001).

The mean difference between the three doses and placebo for reduction in number of arousals was –11.3 (P < .05), –19.4 (P < .001), and –23.7 (P < .001), respectively. And the 6 g at week 3, 7.5 g at week 8, and 9 g at week 13 doses showed significant (P < .001) improvements versus placebo on the ESS (mean difference, –2.1, –3.2, and –3.9, respectively).

All three doses also showed significant improvement in sleep quality and refreshing nature of sleep (P < .001 for all comparisons), as well as improvement of sleep paralysis (P = .04, P = .02, and P = .04, respectively).

There were no significant differences between FT218 and placebo for improvement in hypnagogic hallucinations. Dr. Thorpy noted that the number of patients with baseline hallucinations “was relatively small,” which may have led to this finding. “Had there been a much larger population with hallucinations, I suspect that we would have seen a statistically significant improvement there as well,” he said.

Generally well tolerated

The investigators noted that FT218 was “generally well tolerated, and the most common adverse reactions were well-known and established sodium oxybate adverse reactions.”

Treatment-related AEs that occurred in more than 2% of the patients receiving FT218 included nausea, dizziness, enuresis, headache, decreased appetite, and vomiting.

Seven serious AEs were reported, including five in those assigned to the active treatment. This included one case each of diabetes inadequate control, paresthesia, perirectal abscess, hypertension, and suicidal ideation. Only the case of suicidal ideation was considered to be a treatment-related AE.

The investigators noted that, although they have not yet delved into subgroup analysis to look for differences among sex, age, or race, they plan to do so in the future.

Overall, the results indicate that “FT218 is an effective agent not only for the major symptoms of sleepiness and cataplexy, but also the quality of sleep at night,” said Dr. Thorpy.

Asked whether he thinks the FDA will approve the drug, he said that it should be “straightforward” because it’s just a different formulation of an already-approved agent. “I very much expect there will not be any problems in this medication being approved,” Dr. Thorpy said.

Benefits ‘sleep architecture’

Commenting on the findings, Logan Schneider, MD, codirector of the Stanford/VA Alzheimer’s Center and clinical assistant professor at the Stanford Sleep Center, Redwood City, Calif., said that the investigators’ focus on these secondary outcomes “was really worthwhile.”

Dr. Schneider, who was not involved in the research, noted that, because the study only included patients with narcolepsy, the results can’t be extrapolated to groups who have other sleep disorders.

Still, “it is worthwhile now to expand beyond the two primary symptoms that are, in my consideration, life threatening: daytime sleepiness and cataplexy. We should also address more of the quality of life and other aspects of narcolepsy, including disturbed nocturnal sleep and sleep quality issues related to that,” he said.

“Being able to address those aspects and say, ‘I have a therapy that clearly helps the multidimensionality of our patients’ is very vindicating,” Dr. Schneider noted.

He was also impressed with the various measures the researchers used, rather than relying just on patient reports, “which are subject to recollection difficulties. This was a nice way to quantify possibly as a diagnostic marker the underlying disruption of sleep, as well as a possible treatment marker to show how well a therapy works.”

“It actually shows a beneficial effect on sleep architecture,” Dr. Schneider said.

The study was funded by Avadel Pharmaceuticals. Dr. Thorpy is a consultant/advisory board member for Avadel, Axsome, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, and Takeda Pharmaceutical. Dr. Schneider reports being an adviser and/or on the speakers’ bureau for similar drugs by Jazz Pharmaceuticals and Harmony Biosciences.

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

A novel, once-nightly formulation of sodium oxybate is safe and effective for treating both subjective and objective symptoms of narcolepsy, new research suggests. Top-line results from the phase 3 REST-ON trial released earlier this year showed that the agent known as FT218 (Avadel Pharmaceuticals) met all three of its coprimary efficacy endpoints at all three doses assessed (6 g, 7.5 g, and 9 g). Patients receiving the drug showed significantly greater improvements on the Maintenance of Wakefulness Test (MWT), the Clinical Global Impression of Improvement (CGI-I), and mean weekly attacks of cataplexy, compared with those who received placebo.

The new analyses, which focused on key secondary outcomes, showed that all three doses of the novel agent were associated with significant improvements in sleep quality, refreshing nature of sleep, sleep paralysis, disturbed nocturnal sleep, and scores on the Epworth Sleepiness Scale (ESS).

Principal investigator Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, New York, said in a news release that the results represent “the promise of a potential new treatment strategy for physicians and patients.”

“I am particularly impressed by the consistency of results as early as 3 weeks with only a 6-g dose,” he added.

Dr. Thorpy, who is also a professor of neurology at the Albert Einstein College of Medicine, noted that the new formulation will be more convenient for patients. “The advantage of this medication is its once-nightly formulation, so patients don’t need to awaken during the night and can actually have a better night’s sleep,” he said.

Dr. Thorpy presented the study findings at the 2021 annual meeting of the American Academy of Neurology.

FT218 is currently under review by the U.S. Food and Drug Administration, which has set Oct. 15 as the Prescription Drug User Fee Act target date.

Forced awakening

Sodium oxybate was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy and was expanded in 2005 to also treat excessive daytime sleepiness (EDS). That formulation is indicated for twice-nightly administration, with the second dose taken 2.5-4 hours after the first.

“The need for forced awakening to take the second dose ... may result in noncompliance, which may lead to reduced efficacy and/or mistimed doses,” the investigators noted.

FT218 is a modified-release version of sodium oxybate. A single 6-g dose of the investigational agent “has shown bioequivalent exposure to twice-nightly immediate-release [sodium oxybate] given as two 3-g doses,” wrote the researchers.

It also currently has Orphan Drug Designation from the FDA for the treatment of narcolepsy.

The randomized, double-blind, placebo-controlled, multicenter REST-ON study was conducted from November 2016 to March 2020 and included patients 16 years or older who had narcolepsy type 1 or type 2.

Patients received the active treatment (n = 107; mean age, 30.9 years; 64.5% women) or placebo (n = 105; mean age, 31.6 years; 71.4% women) according to a four-period forced uptitration dosing schedule of 4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and 9 g for 5 weeks.

Secondary outcome measures included the ESS, sleep quality/refreshing nature of sleep on a visual analog scale, sleep paralysis and hypnagogic hallucinations on a sleep symptoms diary, disturbed nocturnal sleep on polysomnographic measures, and number of arousals as defined per the American Academy of Sleep Medicine Score Manual.

Reports of adverse events (AEs) were collected from time of informed consent until 7 days after the last dose received.

Improvement across doses

Results showed that, compared with placebo, improvement in disturbed nocturnal sleep from baseline was significantly greater for the active treatment at 6 g at week 3 (mean between-group difference, –11; P < .001), at 7.5 g at week 8 (mean difference, –17.7; P < .001), and at 9 g at week 13 (mean difference, –22.6; P < .001).

The mean difference between the three doses and placebo for reduction in number of arousals was –11.3 (P < .05), –19.4 (P < .001), and –23.7 (P < .001), respectively. And the 6 g at week 3, 7.5 g at week 8, and 9 g at week 13 doses showed significant (P < .001) improvements versus placebo on the ESS (mean difference, –2.1, –3.2, and –3.9, respectively).

All three doses also showed significant improvement in sleep quality and refreshing nature of sleep (P < .001 for all comparisons), as well as improvement of sleep paralysis (P = .04, P = .02, and P = .04, respectively).

There were no significant differences between FT218 and placebo for improvement in hypnagogic hallucinations. Dr. Thorpy noted that the number of patients with baseline hallucinations “was relatively small,” which may have led to this finding. “Had there been a much larger population with hallucinations, I suspect that we would have seen a statistically significant improvement there as well,” he said.

Generally well tolerated

The investigators noted that FT218 was “generally well tolerated, and the most common adverse reactions were well-known and established sodium oxybate adverse reactions.”

Treatment-related AEs that occurred in more than 2% of the patients receiving FT218 included nausea, dizziness, enuresis, headache, decreased appetite, and vomiting.

Seven serious AEs were reported, including five in those assigned to the active treatment. This included one case each of diabetes inadequate control, paresthesia, perirectal abscess, hypertension, and suicidal ideation. Only the case of suicidal ideation was considered to be a treatment-related AE.

The investigators noted that, although they have not yet delved into subgroup analysis to look for differences among sex, age, or race, they plan to do so in the future.

Overall, the results indicate that “FT218 is an effective agent not only for the major symptoms of sleepiness and cataplexy, but also the quality of sleep at night,” said Dr. Thorpy.

Asked whether he thinks the FDA will approve the drug, he said that it should be “straightforward” because it’s just a different formulation of an already-approved agent. “I very much expect there will not be any problems in this medication being approved,” Dr. Thorpy said.

Benefits ‘sleep architecture’

Commenting on the findings, Logan Schneider, MD, codirector of the Stanford/VA Alzheimer’s Center and clinical assistant professor at the Stanford Sleep Center, Redwood City, Calif., said that the investigators’ focus on these secondary outcomes “was really worthwhile.”

Dr. Schneider, who was not involved in the research, noted that, because the study only included patients with narcolepsy, the results can’t be extrapolated to groups who have other sleep disorders.

Still, “it is worthwhile now to expand beyond the two primary symptoms that are, in my consideration, life threatening: daytime sleepiness and cataplexy. We should also address more of the quality of life and other aspects of narcolepsy, including disturbed nocturnal sleep and sleep quality issues related to that,” he said.

“Being able to address those aspects and say, ‘I have a therapy that clearly helps the multidimensionality of our patients’ is very vindicating,” Dr. Schneider noted.

He was also impressed with the various measures the researchers used, rather than relying just on patient reports, “which are subject to recollection difficulties. This was a nice way to quantify possibly as a diagnostic marker the underlying disruption of sleep, as well as a possible treatment marker to show how well a therapy works.”

“It actually shows a beneficial effect on sleep architecture,” Dr. Schneider said.

The study was funded by Avadel Pharmaceuticals. Dr. Thorpy is a consultant/advisory board member for Avadel, Axsome, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, and Takeda Pharmaceutical. Dr. Schneider reports being an adviser and/or on the speakers’ bureau for similar drugs by Jazz Pharmaceuticals and Harmony Biosciences.

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

A novel, once-nightly formulation of sodium oxybate is safe and effective for treating both subjective and objective symptoms of narcolepsy, new research suggests. Top-line results from the phase 3 REST-ON trial released earlier this year showed that the agent known as FT218 (Avadel Pharmaceuticals) met all three of its coprimary efficacy endpoints at all three doses assessed (6 g, 7.5 g, and 9 g). Patients receiving the drug showed significantly greater improvements on the Maintenance of Wakefulness Test (MWT), the Clinical Global Impression of Improvement (CGI-I), and mean weekly attacks of cataplexy, compared with those who received placebo.

The new analyses, which focused on key secondary outcomes, showed that all three doses of the novel agent were associated with significant improvements in sleep quality, refreshing nature of sleep, sleep paralysis, disturbed nocturnal sleep, and scores on the Epworth Sleepiness Scale (ESS).

Principal investigator Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, New York, said in a news release that the results represent “the promise of a potential new treatment strategy for physicians and patients.”

“I am particularly impressed by the consistency of results as early as 3 weeks with only a 6-g dose,” he added.

Dr. Thorpy, who is also a professor of neurology at the Albert Einstein College of Medicine, noted that the new formulation will be more convenient for patients. “The advantage of this medication is its once-nightly formulation, so patients don’t need to awaken during the night and can actually have a better night’s sleep,” he said.

Dr. Thorpy presented the study findings at the 2021 annual meeting of the American Academy of Neurology.

FT218 is currently under review by the U.S. Food and Drug Administration, which has set Oct. 15 as the Prescription Drug User Fee Act target date.

Forced awakening

Sodium oxybate was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy and was expanded in 2005 to also treat excessive daytime sleepiness (EDS). That formulation is indicated for twice-nightly administration, with the second dose taken 2.5-4 hours after the first.

“The need for forced awakening to take the second dose ... may result in noncompliance, which may lead to reduced efficacy and/or mistimed doses,” the investigators noted.

FT218 is a modified-release version of sodium oxybate. A single 6-g dose of the investigational agent “has shown bioequivalent exposure to twice-nightly immediate-release [sodium oxybate] given as two 3-g doses,” wrote the researchers.

It also currently has Orphan Drug Designation from the FDA for the treatment of narcolepsy.

The randomized, double-blind, placebo-controlled, multicenter REST-ON study was conducted from November 2016 to March 2020 and included patients 16 years or older who had narcolepsy type 1 or type 2.

Patients received the active treatment (n = 107; mean age, 30.9 years; 64.5% women) or placebo (n = 105; mean age, 31.6 years; 71.4% women) according to a four-period forced uptitration dosing schedule of 4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and 9 g for 5 weeks.

Secondary outcome measures included the ESS, sleep quality/refreshing nature of sleep on a visual analog scale, sleep paralysis and hypnagogic hallucinations on a sleep symptoms diary, disturbed nocturnal sleep on polysomnographic measures, and number of arousals as defined per the American Academy of Sleep Medicine Score Manual.

Reports of adverse events (AEs) were collected from time of informed consent until 7 days after the last dose received.

Improvement across doses

Results showed that, compared with placebo, improvement in disturbed nocturnal sleep from baseline was significantly greater for the active treatment at 6 g at week 3 (mean between-group difference, –11; P < .001), at 7.5 g at week 8 (mean difference, –17.7; P < .001), and at 9 g at week 13 (mean difference, –22.6; P < .001).

The mean difference between the three doses and placebo for reduction in number of arousals was –11.3 (P < .05), –19.4 (P < .001), and –23.7 (P < .001), respectively. And the 6 g at week 3, 7.5 g at week 8, and 9 g at week 13 doses showed significant (P < .001) improvements versus placebo on the ESS (mean difference, –2.1, –3.2, and –3.9, respectively).

All three doses also showed significant improvement in sleep quality and refreshing nature of sleep (P < .001 for all comparisons), as well as improvement of sleep paralysis (P = .04, P = .02, and P = .04, respectively).

There were no significant differences between FT218 and placebo for improvement in hypnagogic hallucinations. Dr. Thorpy noted that the number of patients with baseline hallucinations “was relatively small,” which may have led to this finding. “Had there been a much larger population with hallucinations, I suspect that we would have seen a statistically significant improvement there as well,” he said.

Generally well tolerated

The investigators noted that FT218 was “generally well tolerated, and the most common adverse reactions were well-known and established sodium oxybate adverse reactions.”

Treatment-related AEs that occurred in more than 2% of the patients receiving FT218 included nausea, dizziness, enuresis, headache, decreased appetite, and vomiting.

Seven serious AEs were reported, including five in those assigned to the active treatment. This included one case each of diabetes inadequate control, paresthesia, perirectal abscess, hypertension, and suicidal ideation. Only the case of suicidal ideation was considered to be a treatment-related AE.

The investigators noted that, although they have not yet delved into subgroup analysis to look for differences among sex, age, or race, they plan to do so in the future.

Overall, the results indicate that “FT218 is an effective agent not only for the major symptoms of sleepiness and cataplexy, but also the quality of sleep at night,” said Dr. Thorpy.

Asked whether he thinks the FDA will approve the drug, he said that it should be “straightforward” because it’s just a different formulation of an already-approved agent. “I very much expect there will not be any problems in this medication being approved,” Dr. Thorpy said.

Benefits ‘sleep architecture’

Commenting on the findings, Logan Schneider, MD, codirector of the Stanford/VA Alzheimer’s Center and clinical assistant professor at the Stanford Sleep Center, Redwood City, Calif., said that the investigators’ focus on these secondary outcomes “was really worthwhile.”

Dr. Schneider, who was not involved in the research, noted that, because the study only included patients with narcolepsy, the results can’t be extrapolated to groups who have other sleep disorders.

Still, “it is worthwhile now to expand beyond the two primary symptoms that are, in my consideration, life threatening: daytime sleepiness and cataplexy. We should also address more of the quality of life and other aspects of narcolepsy, including disturbed nocturnal sleep and sleep quality issues related to that,” he said.

“Being able to address those aspects and say, ‘I have a therapy that clearly helps the multidimensionality of our patients’ is very vindicating,” Dr. Schneider noted.

He was also impressed with the various measures the researchers used, rather than relying just on patient reports, “which are subject to recollection difficulties. This was a nice way to quantify possibly as a diagnostic marker the underlying disruption of sleep, as well as a possible treatment marker to show how well a therapy works.”

“It actually shows a beneficial effect on sleep architecture,” Dr. Schneider said.

The study was funded by Avadel Pharmaceuticals. Dr. Thorpy is a consultant/advisory board member for Avadel, Axsome, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, and Takeda Pharmaceutical. Dr. Schneider reports being an adviser and/or on the speakers’ bureau for similar drugs by Jazz Pharmaceuticals and Harmony Biosciences.

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

Plasma levels of von Willebrand factor may be a useful biomarker of traumatic brain injury (TBI) and its severity, new research suggests. “Reliable detection of this biomarker at very early time points may allow for prompt TBI detection and therefore intervention,” said study investigator Rachel Elizabeth Thomas, MD, PhD, a neurology resident at the University of Pennsylvania, Philadelphia, while presenting study findings at the American Academy of Neurology’s 2021 annual meeting.

“The level reflects the degree of severity and provides some degree of prognostic information,” she added.
 

A specific marker of acute injury?

Von Willebrand factor is a glycoprotein released in the endothelium in response to local trauma. It plays a part in hemostasis and inflammation and is an indicator of traumatic microvascular injury. Research has shown that it is a biomarker of cerebrovascular pathology. In addition, increased expression of the factor is associated with vascular and neurodegenerative dementia.

The researchers examined whether von Willebrand factor is a biomarker of mild, repetitive TBI. They measured plasma levels of von Willebrand factor in 17 professional boxers before and after boxing bouts.

Eligible participants were between the ages of 18 and 35 years. They had a score of greater than or equal to 1 on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ-3), had competed in at least three 3-minute bouts, and had withstood 25 or more blows to the head.

The investigators compared the plasma levels of von Willebrand factor of the boxers with those of 42 patients who presented to the University of Pennsylvania Trauma Center with TBI and with those of 23 uninjured control persons.

There was no significant difference in plasma levels of von Willebrand factor between boxers before the bout (13.15 µg/mL) and the control persons (6.16 µg/mL). Among the boxers, levels of von Willebrand factor increased by a factor of 1.8 within 30 minutes after bouts, compared with the levels among the control persons. The mean post-bout von Willebrand factor level was 25.09 µg/mL.

“Von Willebrand factor may be more specific for acute injuries, given that it does not seem to stay chronically elevated,” said Dr. Thomas.

In addition, the researchers found a significant positive correlation (r = 0.51; P = .03) between the fold change in plasma von Willebrand factor levels and the number of blows to the head that the athletes sustained.

They also found a significant positive correlation between fold change in von Willebrand factor and RPQ-3 score (r = 0.69; P = .002). These objective and subjective data suggest that levels of von Willebrand factor reflect injury severity, said Dr. Thomas.

Among patients hospitalized with TBI, levels of von Willebrand factor were significantly higher than among control persons (73.2 µg/mL vs. 40.8 µg/mL; P < .0009). The investigators found a linear correlation between plasma von Willebrand factor level and RPQ-3 score (r = 0.24) that was not statistically significant.

Levels of von Willebrand factor among patients hospitalized with TBI were higher on average and demonstrated a greater degree of variability than the levels among boxers immediately after a bout.

“This is not unexpected, given that this group represents a more heterogeneous population with varied forms of acute blunt injury, as compared to the boxers, who have undergone relatively repetitive, milder trauma,” Dr. Thomas said.

The traditional biomarkers of neurotrauma reflect neuronal and glial injury, whereas von Willebrand factor is an indicator of vascular trauma.

“Although on its own, von Willebrand factor is not specific to intracranial vascular injury, paired together with markers such as neurofilament light, GFAP [glial fibrillary acidic protein], and tau, it could be utilized to identify TBI-associated microvascular injury and thus delineate between specific TBI endophenotypes,” said Dr. Thomas. It could distinguish, for example, predominantly neuronal injury from predominantly vascular injury.

Because von Willebrand factor plays a role in the neurovascular unit and is a marker of microvascular injury, the investigators intend to pair measurements of plasma von Willebrand factor with advanced imaging techniques to evaluate cerebral blood flow or cerebrovascular reactivity. Such a study could help determine whether von Willebrand factor levels correlate with the degree of vascular injury and cerebrovascular dysregulation.
 

Point-of-care test?

Commenting on the findings, Kristine O’Phelan, MD, professor of clinical neurology and director of neurocritical care in the department of neurology at the University of Miami, said von Willebrand factor’s likely utility would be as a marker of injury in patients with mild TBI or sports-related concussion.

Imaging and clinical exams do not always reveal these injuries, Dr. O’Phelan added. “Having a biomarker that you can easily test in the blood would be extremely helpful,” she said.

The most exciting part of this study is that it indicates the potential to develop a point-of-care test for use on the athletic field or the battlefield for early detection of mild TBI, she added.

The fact that the test for von Willebrand factor has already been developed is an advantage, said Dr. O’Phelan. The normal and abnormal values of the test are clearly understood. “I do think that they will still need to calibrate it for head injury, because that’s not usually what the test is used for,” said Dr. O’Phelan.

One of the study’s strengths is that the investigators compared patients with TBI with control persons who had exercised, she added, because such a comparison helps clarify the biomarker’s relationship to the injury. Another strength is the application of the test to injuries of various types and of different degrees of severity.

But the biomarker will need to be tested in a larger population, said Dr. O’Phelan. In addition, there is a need to identify the right patient population for this test, as well as the best time frame for its application and potential factors that could confound the test results.

“I do worry a little bit about using early biomarkers for prognosis, particularly in severe TBI, because there’s so many variables that go into outcome,” said Dr. O’Phelan. This test likely would be administered in the first hours after injury, but many factors might affect patients’ outcomes, she added.

One influential factor is age. “If you have a von Willebrand factor of whatever number, that might have different importance in a 30-year-old than in an 80-year-old,” said Dr. O’Phelan. “We need to understand how to interpret those findings better.”

The study was supported by the National Institute for Neurological Disorders and Stroke, the U.S. Department of Defense, and the Pennsylvania Department of Health. Dr. Thomas and Dr. O’Phelan have disclosed no relevant financial relationships.

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

Plasma levels of von Willebrand factor may be a useful biomarker of traumatic brain injury (TBI) and its severity, new research suggests. “Reliable detection of this biomarker at very early time points may allow for prompt TBI detection and therefore intervention,” said study investigator Rachel Elizabeth Thomas, MD, PhD, a neurology resident at the University of Pennsylvania, Philadelphia, while presenting study findings at the American Academy of Neurology’s 2021 annual meeting.

“The level reflects the degree of severity and provides some degree of prognostic information,” she added.
 

A specific marker of acute injury?

Von Willebrand factor is a glycoprotein released in the endothelium in response to local trauma. It plays a part in hemostasis and inflammation and is an indicator of traumatic microvascular injury. Research has shown that it is a biomarker of cerebrovascular pathology. In addition, increased expression of the factor is associated with vascular and neurodegenerative dementia.

The researchers examined whether von Willebrand factor is a biomarker of mild, repetitive TBI. They measured plasma levels of von Willebrand factor in 17 professional boxers before and after boxing bouts.

Eligible participants were between the ages of 18 and 35 years. They had a score of greater than or equal to 1 on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ-3), had competed in at least three 3-minute bouts, and had withstood 25 or more blows to the head.

The investigators compared the plasma levels of von Willebrand factor of the boxers with those of 42 patients who presented to the University of Pennsylvania Trauma Center with TBI and with those of 23 uninjured control persons.

There was no significant difference in plasma levels of von Willebrand factor between boxers before the bout (13.15 µg/mL) and the control persons (6.16 µg/mL). Among the boxers, levels of von Willebrand factor increased by a factor of 1.8 within 30 minutes after bouts, compared with the levels among the control persons. The mean post-bout von Willebrand factor level was 25.09 µg/mL.

“Von Willebrand factor may be more specific for acute injuries, given that it does not seem to stay chronically elevated,” said Dr. Thomas.

In addition, the researchers found a significant positive correlation (r = 0.51; P = .03) between the fold change in plasma von Willebrand factor levels and the number of blows to the head that the athletes sustained.

They also found a significant positive correlation between fold change in von Willebrand factor and RPQ-3 score (r = 0.69; P = .002). These objective and subjective data suggest that levels of von Willebrand factor reflect injury severity, said Dr. Thomas.

Among patients hospitalized with TBI, levels of von Willebrand factor were significantly higher than among control persons (73.2 µg/mL vs. 40.8 µg/mL; P < .0009). The investigators found a linear correlation between plasma von Willebrand factor level and RPQ-3 score (r = 0.24) that was not statistically significant.

Levels of von Willebrand factor among patients hospitalized with TBI were higher on average and demonstrated a greater degree of variability than the levels among boxers immediately after a bout.

“This is not unexpected, given that this group represents a more heterogeneous population with varied forms of acute blunt injury, as compared to the boxers, who have undergone relatively repetitive, milder trauma,” Dr. Thomas said.

The traditional biomarkers of neurotrauma reflect neuronal and glial injury, whereas von Willebrand factor is an indicator of vascular trauma.

“Although on its own, von Willebrand factor is not specific to intracranial vascular injury, paired together with markers such as neurofilament light, GFAP [glial fibrillary acidic protein], and tau, it could be utilized to identify TBI-associated microvascular injury and thus delineate between specific TBI endophenotypes,” said Dr. Thomas. It could distinguish, for example, predominantly neuronal injury from predominantly vascular injury.

Because von Willebrand factor plays a role in the neurovascular unit and is a marker of microvascular injury, the investigators intend to pair measurements of plasma von Willebrand factor with advanced imaging techniques to evaluate cerebral blood flow or cerebrovascular reactivity. Such a study could help determine whether von Willebrand factor levels correlate with the degree of vascular injury and cerebrovascular dysregulation.
 

Point-of-care test?

Commenting on the findings, Kristine O’Phelan, MD, professor of clinical neurology and director of neurocritical care in the department of neurology at the University of Miami, said von Willebrand factor’s likely utility would be as a marker of injury in patients with mild TBI or sports-related concussion.

Imaging and clinical exams do not always reveal these injuries, Dr. O’Phelan added. “Having a biomarker that you can easily test in the blood would be extremely helpful,” she said.

The most exciting part of this study is that it indicates the potential to develop a point-of-care test for use on the athletic field or the battlefield for early detection of mild TBI, she added.

The fact that the test for von Willebrand factor has already been developed is an advantage, said Dr. O’Phelan. The normal and abnormal values of the test are clearly understood. “I do think that they will still need to calibrate it for head injury, because that’s not usually what the test is used for,” said Dr. O’Phelan.

One of the study’s strengths is that the investigators compared patients with TBI with control persons who had exercised, she added, because such a comparison helps clarify the biomarker’s relationship to the injury. Another strength is the application of the test to injuries of various types and of different degrees of severity.

But the biomarker will need to be tested in a larger population, said Dr. O’Phelan. In addition, there is a need to identify the right patient population for this test, as well as the best time frame for its application and potential factors that could confound the test results.

“I do worry a little bit about using early biomarkers for prognosis, particularly in severe TBI, because there’s so many variables that go into outcome,” said Dr. O’Phelan. This test likely would be administered in the first hours after injury, but many factors might affect patients’ outcomes, she added.

One influential factor is age. “If you have a von Willebrand factor of whatever number, that might have different importance in a 30-year-old than in an 80-year-old,” said Dr. O’Phelan. “We need to understand how to interpret those findings better.”

The study was supported by the National Institute for Neurological Disorders and Stroke, the U.S. Department of Defense, and the Pennsylvania Department of Health. Dr. Thomas and Dr. O’Phelan have disclosed no relevant financial relationships.

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

Plasma levels of von Willebrand factor may be a useful biomarker of traumatic brain injury (TBI) and its severity, new research suggests. “Reliable detection of this biomarker at very early time points may allow for prompt TBI detection and therefore intervention,” said study investigator Rachel Elizabeth Thomas, MD, PhD, a neurology resident at the University of Pennsylvania, Philadelphia, while presenting study findings at the American Academy of Neurology’s 2021 annual meeting.

“The level reflects the degree of severity and provides some degree of prognostic information,” she added.
 

A specific marker of acute injury?

Von Willebrand factor is a glycoprotein released in the endothelium in response to local trauma. It plays a part in hemostasis and inflammation and is an indicator of traumatic microvascular injury. Research has shown that it is a biomarker of cerebrovascular pathology. In addition, increased expression of the factor is associated with vascular and neurodegenerative dementia.

The researchers examined whether von Willebrand factor is a biomarker of mild, repetitive TBI. They measured plasma levels of von Willebrand factor in 17 professional boxers before and after boxing bouts.

Eligible participants were between the ages of 18 and 35 years. They had a score of greater than or equal to 1 on the Rivermead Post-Concussion Symptoms Questionnaire (RPQ-3), had competed in at least three 3-minute bouts, and had withstood 25 or more blows to the head.

The investigators compared the plasma levels of von Willebrand factor of the boxers with those of 42 patients who presented to the University of Pennsylvania Trauma Center with TBI and with those of 23 uninjured control persons.

There was no significant difference in plasma levels of von Willebrand factor between boxers before the bout (13.15 µg/mL) and the control persons (6.16 µg/mL). Among the boxers, levels of von Willebrand factor increased by a factor of 1.8 within 30 minutes after bouts, compared with the levels among the control persons. The mean post-bout von Willebrand factor level was 25.09 µg/mL.

“Von Willebrand factor may be more specific for acute injuries, given that it does not seem to stay chronically elevated,” said Dr. Thomas.

In addition, the researchers found a significant positive correlation (r = 0.51; P = .03) between the fold change in plasma von Willebrand factor levels and the number of blows to the head that the athletes sustained.

They also found a significant positive correlation between fold change in von Willebrand factor and RPQ-3 score (r = 0.69; P = .002). These objective and subjective data suggest that levels of von Willebrand factor reflect injury severity, said Dr. Thomas.

Among patients hospitalized with TBI, levels of von Willebrand factor were significantly higher than among control persons (73.2 µg/mL vs. 40.8 µg/mL; P < .0009). The investigators found a linear correlation between plasma von Willebrand factor level and RPQ-3 score (r = 0.24) that was not statistically significant.

Levels of von Willebrand factor among patients hospitalized with TBI were higher on average and demonstrated a greater degree of variability than the levels among boxers immediately after a bout.

“This is not unexpected, given that this group represents a more heterogeneous population with varied forms of acute blunt injury, as compared to the boxers, who have undergone relatively repetitive, milder trauma,” Dr. Thomas said.

The traditional biomarkers of neurotrauma reflect neuronal and glial injury, whereas von Willebrand factor is an indicator of vascular trauma.

“Although on its own, von Willebrand factor is not specific to intracranial vascular injury, paired together with markers such as neurofilament light, GFAP [glial fibrillary acidic protein], and tau, it could be utilized to identify TBI-associated microvascular injury and thus delineate between specific TBI endophenotypes,” said Dr. Thomas. It could distinguish, for example, predominantly neuronal injury from predominantly vascular injury.

Because von Willebrand factor plays a role in the neurovascular unit and is a marker of microvascular injury, the investigators intend to pair measurements of plasma von Willebrand factor with advanced imaging techniques to evaluate cerebral blood flow or cerebrovascular reactivity. Such a study could help determine whether von Willebrand factor levels correlate with the degree of vascular injury and cerebrovascular dysregulation.
 

Point-of-care test?

Commenting on the findings, Kristine O’Phelan, MD, professor of clinical neurology and director of neurocritical care in the department of neurology at the University of Miami, said von Willebrand factor’s likely utility would be as a marker of injury in patients with mild TBI or sports-related concussion.

Imaging and clinical exams do not always reveal these injuries, Dr. O’Phelan added. “Having a biomarker that you can easily test in the blood would be extremely helpful,” she said.

The most exciting part of this study is that it indicates the potential to develop a point-of-care test for use on the athletic field or the battlefield for early detection of mild TBI, she added.

The fact that the test for von Willebrand factor has already been developed is an advantage, said Dr. O’Phelan. The normal and abnormal values of the test are clearly understood. “I do think that they will still need to calibrate it for head injury, because that’s not usually what the test is used for,” said Dr. O’Phelan.

One of the study’s strengths is that the investigators compared patients with TBI with control persons who had exercised, she added, because such a comparison helps clarify the biomarker’s relationship to the injury. Another strength is the application of the test to injuries of various types and of different degrees of severity.

But the biomarker will need to be tested in a larger population, said Dr. O’Phelan. In addition, there is a need to identify the right patient population for this test, as well as the best time frame for its application and potential factors that could confound the test results.

“I do worry a little bit about using early biomarkers for prognosis, particularly in severe TBI, because there’s so many variables that go into outcome,” said Dr. O’Phelan. This test likely would be administered in the first hours after injury, but many factors might affect patients’ outcomes, she added.

One influential factor is age. “If you have a von Willebrand factor of whatever number, that might have different importance in a 30-year-old than in an 80-year-old,” said Dr. O’Phelan. “We need to understand how to interpret those findings better.”

The study was supported by the National Institute for Neurological Disorders and Stroke, the U.S. Department of Defense, and the Pennsylvania Department of Health. Dr. Thomas and Dr. O’Phelan have disclosed no relevant financial relationships.

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

Plasma levels of neurofilament light (NfL) are a better predictor of cognitive decline and changes in neuroimaging in comparison with total tau (T-tau), new research suggests. In certain contexts, T-tau improves cross-sectional analyses of these outcomes, but adding T-tau measurements to NfL measurements does not improve the predictive power of NfL, results of a longitudinal analysis show.

“The major distinction, for cognition at least, was that NfL cross-sectionally was associated with most cognitive outcomes, and longitudinally, higher NfL at baseline was associated with cognitive decline in every domain,” said study investigator Jordan Marks, an MD/PhD student at the Mayo Medical School, Rochester, Minn.

The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
 

New tool for dementia diagnosis?

In recent years, researchers have studied NfL and T-tau as potential blood-based biomarkers of neurodegeneration. In cross-sectional and longitudinal studies, NfL and T-tau have been associated with worse cognition and with neuroimaging measures of cortical thickness, cortical atrophy, white-matter hyperintensity, and white-matter integrity. However, no previous research has directly compared the prognostic ability of these two biomarkers.

The study included 995 participants without dementia in the Mayo Clinic Study on Aging. All participants underwent measurement of NfL and T-tau and assessment of cognitive status, as well as neuroimaging. The investigators measured NfL and T-tau on the Simoa HD-1 platform. They reexamined patients approximately every 15 months. The median follow-up time was 6.2 years.

To examine associations between baseline plasma NfL or T-tau and cognitive or neuroimaging outcomes, the researchers conducted data analyses using linear mixed effects models and adjusted the data for age, sex, and education. They replicated these analyses using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). For these analyses, they selected 387 participants without dementia who had been followed for a median of 3.0 years.

In all analyses, baseline plasma NfL was more strongly associated with cognitive and neuroimaging outcomes than T-tau. “Baseline plasma NfL was associated with cognitive decline in all domains measured, while T-tau was not associated with cognitive decline,” said Mr. Marks.

Plasma NfL was more strongly associated with decreases in cortical thickness over time than T-tau was. NfL was also more strongly associated with declining hippocampal volume and white-matter changes.

However, in cross-sectional analysis, the combination of elevated NfL levels and elevated T-tau levels at baseline was more strongly associated with decreased global cognition and memory, compared with elevated NfL levels alone. The combination also was more strongly associated with neuroimaging measures, such as temporal cortex thickness and increased number of infarcts. However, in longitudinal analyses, T-tau did not add to the predictive value of NfL.

The analyses using ADNI data yielded similar results. Overall, the results suggest that NfL is a better prognostic marker of neurodegeneration in general, said Mr. Marks.

These findings, he said, may have implications for screening and diagnosis. “I’m definitely hopeful that NfL will be useful in a clinical setting to screen for those at risk of dementia and will be helpful, along with other modalities, like cognitive testing, for dementia diagnosis,” said Mr. Marks.

Future research should examine how changes in these biomarkers are associated with cognitive and neuroimaging outcomes over time.

“We used plasma levels at one point in time in this study, but we need a better sense of how to interpret, for example, what a rise in plasma NfL over a certain time period means for someone’s risk of developing neurodegenerative disease,” Mr. Marks added.
 

An ‘exciting’ prospect

Commenting on the study, Glen R. Finney, MD, director of the Memory and Cognition Program for Geisinger Health in Wilkes-Barre, Pa., said the findings add to neurologists’ ability to screen for brain diseases. “Evidence of neurodegeneration is part of the modern diagnosis of several disorders. While brain imaging can also provide that and may be needed for other reasons, this could provide an easy, potentially inexpensive way to screen for damage to the brain, giving us an added tool,” said Dr. Finney.

The prospect of using blood plasma markers to explore disease of the brain is exciting, Dr. Finney added. “I would like to see ongoing refinement of this approach and would like to see if there’s other markers in blood that could be used to find what specifically may be causing the damage,” he said.

The study was funded by the National Institutes of Health, the National Institute on Aging, and the GHR Foundation. Mr. Marks and Dr. Finney have disclosed no relevant financial relationships.

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

Plasma levels of neurofilament light (NfL) are a better predictor of cognitive decline and changes in neuroimaging in comparison with total tau (T-tau), new research suggests. In certain contexts, T-tau improves cross-sectional analyses of these outcomes, but adding T-tau measurements to NfL measurements does not improve the predictive power of NfL, results of a longitudinal analysis show.

“The major distinction, for cognition at least, was that NfL cross-sectionally was associated with most cognitive outcomes, and longitudinally, higher NfL at baseline was associated with cognitive decline in every domain,” said study investigator Jordan Marks, an MD/PhD student at the Mayo Medical School, Rochester, Minn.

The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
 

New tool for dementia diagnosis?

In recent years, researchers have studied NfL and T-tau as potential blood-based biomarkers of neurodegeneration. In cross-sectional and longitudinal studies, NfL and T-tau have been associated with worse cognition and with neuroimaging measures of cortical thickness, cortical atrophy, white-matter hyperintensity, and white-matter integrity. However, no previous research has directly compared the prognostic ability of these two biomarkers.

The study included 995 participants without dementia in the Mayo Clinic Study on Aging. All participants underwent measurement of NfL and T-tau and assessment of cognitive status, as well as neuroimaging. The investigators measured NfL and T-tau on the Simoa HD-1 platform. They reexamined patients approximately every 15 months. The median follow-up time was 6.2 years.

To examine associations between baseline plasma NfL or T-tau and cognitive or neuroimaging outcomes, the researchers conducted data analyses using linear mixed effects models and adjusted the data for age, sex, and education. They replicated these analyses using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). For these analyses, they selected 387 participants without dementia who had been followed for a median of 3.0 years.

In all analyses, baseline plasma NfL was more strongly associated with cognitive and neuroimaging outcomes than T-tau. “Baseline plasma NfL was associated with cognitive decline in all domains measured, while T-tau was not associated with cognitive decline,” said Mr. Marks.

Plasma NfL was more strongly associated with decreases in cortical thickness over time than T-tau was. NfL was also more strongly associated with declining hippocampal volume and white-matter changes.

However, in cross-sectional analysis, the combination of elevated NfL levels and elevated T-tau levels at baseline was more strongly associated with decreased global cognition and memory, compared with elevated NfL levels alone. The combination also was more strongly associated with neuroimaging measures, such as temporal cortex thickness and increased number of infarcts. However, in longitudinal analyses, T-tau did not add to the predictive value of NfL.

The analyses using ADNI data yielded similar results. Overall, the results suggest that NfL is a better prognostic marker of neurodegeneration in general, said Mr. Marks.

These findings, he said, may have implications for screening and diagnosis. “I’m definitely hopeful that NfL will be useful in a clinical setting to screen for those at risk of dementia and will be helpful, along with other modalities, like cognitive testing, for dementia diagnosis,” said Mr. Marks.

Future research should examine how changes in these biomarkers are associated with cognitive and neuroimaging outcomes over time.

“We used plasma levels at one point in time in this study, but we need a better sense of how to interpret, for example, what a rise in plasma NfL over a certain time period means for someone’s risk of developing neurodegenerative disease,” Mr. Marks added.
 

An ‘exciting’ prospect

Commenting on the study, Glen R. Finney, MD, director of the Memory and Cognition Program for Geisinger Health in Wilkes-Barre, Pa., said the findings add to neurologists’ ability to screen for brain diseases. “Evidence of neurodegeneration is part of the modern diagnosis of several disorders. While brain imaging can also provide that and may be needed for other reasons, this could provide an easy, potentially inexpensive way to screen for damage to the brain, giving us an added tool,” said Dr. Finney.

The prospect of using blood plasma markers to explore disease of the brain is exciting, Dr. Finney added. “I would like to see ongoing refinement of this approach and would like to see if there’s other markers in blood that could be used to find what specifically may be causing the damage,” he said.

The study was funded by the National Institutes of Health, the National Institute on Aging, and the GHR Foundation. Mr. Marks and Dr. Finney have disclosed no relevant financial relationships.

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

Plasma levels of neurofilament light (NfL) are a better predictor of cognitive decline and changes in neuroimaging in comparison with total tau (T-tau), new research suggests. In certain contexts, T-tau improves cross-sectional analyses of these outcomes, but adding T-tau measurements to NfL measurements does not improve the predictive power of NfL, results of a longitudinal analysis show.

“The major distinction, for cognition at least, was that NfL cross-sectionally was associated with most cognitive outcomes, and longitudinally, higher NfL at baseline was associated with cognitive decline in every domain,” said study investigator Jordan Marks, an MD/PhD student at the Mayo Medical School, Rochester, Minn.

The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
 

New tool for dementia diagnosis?

In recent years, researchers have studied NfL and T-tau as potential blood-based biomarkers of neurodegeneration. In cross-sectional and longitudinal studies, NfL and T-tau have been associated with worse cognition and with neuroimaging measures of cortical thickness, cortical atrophy, white-matter hyperintensity, and white-matter integrity. However, no previous research has directly compared the prognostic ability of these two biomarkers.

The study included 995 participants without dementia in the Mayo Clinic Study on Aging. All participants underwent measurement of NfL and T-tau and assessment of cognitive status, as well as neuroimaging. The investigators measured NfL and T-tau on the Simoa HD-1 platform. They reexamined patients approximately every 15 months. The median follow-up time was 6.2 years.

To examine associations between baseline plasma NfL or T-tau and cognitive or neuroimaging outcomes, the researchers conducted data analyses using linear mixed effects models and adjusted the data for age, sex, and education. They replicated these analyses using data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). For these analyses, they selected 387 participants without dementia who had been followed for a median of 3.0 years.

In all analyses, baseline plasma NfL was more strongly associated with cognitive and neuroimaging outcomes than T-tau. “Baseline plasma NfL was associated with cognitive decline in all domains measured, while T-tau was not associated with cognitive decline,” said Mr. Marks.

Plasma NfL was more strongly associated with decreases in cortical thickness over time than T-tau was. NfL was also more strongly associated with declining hippocampal volume and white-matter changes.

However, in cross-sectional analysis, the combination of elevated NfL levels and elevated T-tau levels at baseline was more strongly associated with decreased global cognition and memory, compared with elevated NfL levels alone. The combination also was more strongly associated with neuroimaging measures, such as temporal cortex thickness and increased number of infarcts. However, in longitudinal analyses, T-tau did not add to the predictive value of NfL.

The analyses using ADNI data yielded similar results. Overall, the results suggest that NfL is a better prognostic marker of neurodegeneration in general, said Mr. Marks.

These findings, he said, may have implications for screening and diagnosis. “I’m definitely hopeful that NfL will be useful in a clinical setting to screen for those at risk of dementia and will be helpful, along with other modalities, like cognitive testing, for dementia diagnosis,” said Mr. Marks.

Future research should examine how changes in these biomarkers are associated with cognitive and neuroimaging outcomes over time.

“We used plasma levels at one point in time in this study, but we need a better sense of how to interpret, for example, what a rise in plasma NfL over a certain time period means for someone’s risk of developing neurodegenerative disease,” Mr. Marks added.
 

An ‘exciting’ prospect

Commenting on the study, Glen R. Finney, MD, director of the Memory and Cognition Program for Geisinger Health in Wilkes-Barre, Pa., said the findings add to neurologists’ ability to screen for brain diseases. “Evidence of neurodegeneration is part of the modern diagnosis of several disorders. While brain imaging can also provide that and may be needed for other reasons, this could provide an easy, potentially inexpensive way to screen for damage to the brain, giving us an added tool,” said Dr. Finney.

The prospect of using blood plasma markers to explore disease of the brain is exciting, Dr. Finney added. “I would like to see ongoing refinement of this approach and would like to see if there’s other markers in blood that could be used to find what specifically may be causing the damage,” he said.

The study was funded by the National Institutes of Health, the National Institute on Aging, and the GHR Foundation. Mr. Marks and Dr. Finney have disclosed no relevant financial relationships.

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

The investigational drug tolebrutinib effectively reduces brain lesions in patients with highly active relapsing remitting multiple sclerosis (MS), new research suggests. After 12 weeks of treatment, MRI revealed the drug, a Bruton tyrosine kinase inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and an 89% reduction in new and enlarging T2 lesions, compared with placebo.

The analysis supports that tolebrutinib is as effective in this group of patients with highly active relapsing remitting MS as it is in the overall patient population, study investigator said Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia, Vancouver.

“What is additionally exciting is that this effect was seen within a relatively short period of time – within 3 months. This will be important for patients and physicians to know how soon to expect a treatment to work if they have high-risk baseline features,” he added.

The findings were presented at the 2021 annual meeting of the American Academy of Neurology.
 

New drug class

BTK inhibitors are a new class of oral therapies, and phase 2 trials in patients with relapsing remitting MS show they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk for lymphopenia or immunoglobulin depletion.

Tolebrutinib is a covalent, irreversible BTK inhibitor that penetrates the central nervous system well. In a previous randomized, double-blind, phase 2b trial, it was well tolerated and was associated with a dose-dependent reduction in new or enlarging MRI lesions. Of the four doses studied, the 60-mg dose was the most effective.

Because highly active MS is associated with a more aggressive disease course, the investigators examined tolebrutinib’s efficacy and safety in patients with highly active disease who were participants in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.

The investigators defined highly active disease as one relapse in the year before screening and one or more gadolinium-enhancing lesions on MRI performed within 6 months before screening, or nine or more T2 lesions at baseline, or two or more relapses in the year before screening.

Of the 130 participants enrolled in the study, 61 (47%) met criteria for highly active disease at baseline. These patients represented 44% of the placebo group (29 of 66 participants) who later crossed over to tolebrutinib treatment.

At baseline, demographics in patients with highly active disease were similar to those of the overall study population, although it was slightly younger with slightly shorter disease duration, slightly less disability, and a greater likelihood of gadolinium-enhancing lesions at baseline versus the overall study population.

The proportion of patients with highly active disease was 36% in the 5-mg group, 59% in the 15-mg group, 48% in the 30-mg group, and 44% in the 60-mg group.

The study’s primary objective was to examine the dose-response relationship after 12 weeks of treatment with tolebrutinib.
 

Good safety, tolerability

After 12 weeks, the mean number of new gadolinium-enhancing lesions in patients with highly active disease was 0.82 in the 5-mg group, 0.50 in the 15-mg group, 0.38 in the 30-mg group, and 0.08 in the 60-mg group. The corresponding measurements in the overall study population were 1.39 in the 5-mg group, 0.77 in the 15-mg group, 0.76 in the 30-mg group, and 0.13 in the 60-mg group.

After 12 weeks, numbers of new or enlarging T2 lesions among patients with highly active disease were 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg) and 0.15 (60 mg). The corresponding measurements in the overall population were 1.90 (5 mg), 1.32 (15 mg) 1.30 (30 mg) and 0.23 (60 mg).

Tolebrutinib had excellent safety and tolerability in patients with highly active disease and in the overall population, said Dr. Traboulsee.

No adverse events were linked to the study drug. One patient with highly active disease who received 60 mg of tolebrutinib had transient elevated ALT levels greater than three times the upper limit of normal. This patient also previously had elevated ALT at baseline.

One serious adverse event occurred during the study. One patient was hospitalized for MS relapse. The patient had been assigned to the 60-mg dose of tolebrutinib. The patient recovered and remained on study treatment.

Two independent studies have indicated that BTK inhibition is an effective treatment approach for relapsing remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.

“Most, if not all, MS therapies mostly affect the peripheral immune system, preventing autoreactive lymphocytes crossing the blood-brain barrier and causing damage,” said Dr. Traboulsee.

Therapies that enter the CNS can target abnormal immune cells, including microglia that are believed to promote disease progression. “If this is an important target, then we now have a highly CNS-penetrant drug that could potentially change the course of progression,” said Dr. Traboulsee.

Serum biomarkers and advanced imaging data collected during the phase 2 trial could help clarify the mechanisms of disease progression and the effects of tolebrutinib, he added. “Ultimately though, it is the clinical outcomes in the phase 3 programs that are essential to know where to place tolebrutinib in the future care of relapsing and progressive forms of MS.”
 

Not an unmet need

Commenting on the findings, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania, Philadelphia, said there are several available treatments that effectively suppress clinical and radiologic evidence of acute inflammation in relapsing remitting MS.

“Any new drug that is to be added to that pharmacological armamentarium should have distinct advantages over what is currently available. Treating relapsing remitting MS is not, in my opinion, an unmet need in MS; treating progressive disease is,” he said.

Dr. Berger said that tolebrutinib appears to be better than placebo in suppressing disease activity, particularly at higher doses. “However, the study is small – only 61 patients,” noted Dr. Berger, who was not involved in the study.

In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.

“As there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib needs to be tempered with that in mind,” said Dr. Berger.

Evaluating how tolebrutinib compares with other BTK inhibitors will require a head-to-head trial. “I’d be more interested in whether the drug has an effect on progressive disease,” Dr. Berger concluded.

The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Dr. Traboulsee has received research grant support, honoraria for consulting, and honoraria for participating in a speakers’ bureau from Sanofi Genzyme. Dr. Berger disclosed no relevant financial relationships.

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

The investigational drug tolebrutinib effectively reduces brain lesions in patients with highly active relapsing remitting multiple sclerosis (MS), new research suggests. After 12 weeks of treatment, MRI revealed the drug, a Bruton tyrosine kinase inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and an 89% reduction in new and enlarging T2 lesions, compared with placebo.

The analysis supports that tolebrutinib is as effective in this group of patients with highly active relapsing remitting MS as it is in the overall patient population, study investigator said Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia, Vancouver.

“What is additionally exciting is that this effect was seen within a relatively short period of time – within 3 months. This will be important for patients and physicians to know how soon to expect a treatment to work if they have high-risk baseline features,” he added.

The findings were presented at the 2021 annual meeting of the American Academy of Neurology.
 

New drug class

BTK inhibitors are a new class of oral therapies, and phase 2 trials in patients with relapsing remitting MS show they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk for lymphopenia or immunoglobulin depletion.

Tolebrutinib is a covalent, irreversible BTK inhibitor that penetrates the central nervous system well. In a previous randomized, double-blind, phase 2b trial, it was well tolerated and was associated with a dose-dependent reduction in new or enlarging MRI lesions. Of the four doses studied, the 60-mg dose was the most effective.

Because highly active MS is associated with a more aggressive disease course, the investigators examined tolebrutinib’s efficacy and safety in patients with highly active disease who were participants in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.

The investigators defined highly active disease as one relapse in the year before screening and one or more gadolinium-enhancing lesions on MRI performed within 6 months before screening, or nine or more T2 lesions at baseline, or two or more relapses in the year before screening.

Of the 130 participants enrolled in the study, 61 (47%) met criteria for highly active disease at baseline. These patients represented 44% of the placebo group (29 of 66 participants) who later crossed over to tolebrutinib treatment.

At baseline, demographics in patients with highly active disease were similar to those of the overall study population, although it was slightly younger with slightly shorter disease duration, slightly less disability, and a greater likelihood of gadolinium-enhancing lesions at baseline versus the overall study population.

The proportion of patients with highly active disease was 36% in the 5-mg group, 59% in the 15-mg group, 48% in the 30-mg group, and 44% in the 60-mg group.

The study’s primary objective was to examine the dose-response relationship after 12 weeks of treatment with tolebrutinib.
 

Good safety, tolerability

After 12 weeks, the mean number of new gadolinium-enhancing lesions in patients with highly active disease was 0.82 in the 5-mg group, 0.50 in the 15-mg group, 0.38 in the 30-mg group, and 0.08 in the 60-mg group. The corresponding measurements in the overall study population were 1.39 in the 5-mg group, 0.77 in the 15-mg group, 0.76 in the 30-mg group, and 0.13 in the 60-mg group.

After 12 weeks, numbers of new or enlarging T2 lesions among patients with highly active disease were 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg) and 0.15 (60 mg). The corresponding measurements in the overall population were 1.90 (5 mg), 1.32 (15 mg) 1.30 (30 mg) and 0.23 (60 mg).

Tolebrutinib had excellent safety and tolerability in patients with highly active disease and in the overall population, said Dr. Traboulsee.

No adverse events were linked to the study drug. One patient with highly active disease who received 60 mg of tolebrutinib had transient elevated ALT levels greater than three times the upper limit of normal. This patient also previously had elevated ALT at baseline.

One serious adverse event occurred during the study. One patient was hospitalized for MS relapse. The patient had been assigned to the 60-mg dose of tolebrutinib. The patient recovered and remained on study treatment.

Two independent studies have indicated that BTK inhibition is an effective treatment approach for relapsing remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.

“Most, if not all, MS therapies mostly affect the peripheral immune system, preventing autoreactive lymphocytes crossing the blood-brain barrier and causing damage,” said Dr. Traboulsee.

Therapies that enter the CNS can target abnormal immune cells, including microglia that are believed to promote disease progression. “If this is an important target, then we now have a highly CNS-penetrant drug that could potentially change the course of progression,” said Dr. Traboulsee.

Serum biomarkers and advanced imaging data collected during the phase 2 trial could help clarify the mechanisms of disease progression and the effects of tolebrutinib, he added. “Ultimately though, it is the clinical outcomes in the phase 3 programs that are essential to know where to place tolebrutinib in the future care of relapsing and progressive forms of MS.”
 

Not an unmet need

Commenting on the findings, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania, Philadelphia, said there are several available treatments that effectively suppress clinical and radiologic evidence of acute inflammation in relapsing remitting MS.

“Any new drug that is to be added to that pharmacological armamentarium should have distinct advantages over what is currently available. Treating relapsing remitting MS is not, in my opinion, an unmet need in MS; treating progressive disease is,” he said.

Dr. Berger said that tolebrutinib appears to be better than placebo in suppressing disease activity, particularly at higher doses. “However, the study is small – only 61 patients,” noted Dr. Berger, who was not involved in the study.

In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.

“As there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib needs to be tempered with that in mind,” said Dr. Berger.

Evaluating how tolebrutinib compares with other BTK inhibitors will require a head-to-head trial. “I’d be more interested in whether the drug has an effect on progressive disease,” Dr. Berger concluded.

The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Dr. Traboulsee has received research grant support, honoraria for consulting, and honoraria for participating in a speakers’ bureau from Sanofi Genzyme. Dr. Berger disclosed no relevant financial relationships.

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

The investigational drug tolebrutinib effectively reduces brain lesions in patients with highly active relapsing remitting multiple sclerosis (MS), new research suggests. After 12 weeks of treatment, MRI revealed the drug, a Bruton tyrosine kinase inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and an 89% reduction in new and enlarging T2 lesions, compared with placebo.

The analysis supports that tolebrutinib is as effective in this group of patients with highly active relapsing remitting MS as it is in the overall patient population, study investigator said Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia, Vancouver.

“What is additionally exciting is that this effect was seen within a relatively short period of time – within 3 months. This will be important for patients and physicians to know how soon to expect a treatment to work if they have high-risk baseline features,” he added.

The findings were presented at the 2021 annual meeting of the American Academy of Neurology.
 

New drug class

BTK inhibitors are a new class of oral therapies, and phase 2 trials in patients with relapsing remitting MS show they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk for lymphopenia or immunoglobulin depletion.

Tolebrutinib is a covalent, irreversible BTK inhibitor that penetrates the central nervous system well. In a previous randomized, double-blind, phase 2b trial, it was well tolerated and was associated with a dose-dependent reduction in new or enlarging MRI lesions. Of the four doses studied, the 60-mg dose was the most effective.

Because highly active MS is associated with a more aggressive disease course, the investigators examined tolebrutinib’s efficacy and safety in patients with highly active disease who were participants in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.

The investigators defined highly active disease as one relapse in the year before screening and one or more gadolinium-enhancing lesions on MRI performed within 6 months before screening, or nine or more T2 lesions at baseline, or two or more relapses in the year before screening.

Of the 130 participants enrolled in the study, 61 (47%) met criteria for highly active disease at baseline. These patients represented 44% of the placebo group (29 of 66 participants) who later crossed over to tolebrutinib treatment.

At baseline, demographics in patients with highly active disease were similar to those of the overall study population, although it was slightly younger with slightly shorter disease duration, slightly less disability, and a greater likelihood of gadolinium-enhancing lesions at baseline versus the overall study population.

The proportion of patients with highly active disease was 36% in the 5-mg group, 59% in the 15-mg group, 48% in the 30-mg group, and 44% in the 60-mg group.

The study’s primary objective was to examine the dose-response relationship after 12 weeks of treatment with tolebrutinib.
 

Good safety, tolerability

After 12 weeks, the mean number of new gadolinium-enhancing lesions in patients with highly active disease was 0.82 in the 5-mg group, 0.50 in the 15-mg group, 0.38 in the 30-mg group, and 0.08 in the 60-mg group. The corresponding measurements in the overall study population were 1.39 in the 5-mg group, 0.77 in the 15-mg group, 0.76 in the 30-mg group, and 0.13 in the 60-mg group.

After 12 weeks, numbers of new or enlarging T2 lesions among patients with highly active disease were 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg) and 0.15 (60 mg). The corresponding measurements in the overall population were 1.90 (5 mg), 1.32 (15 mg) 1.30 (30 mg) and 0.23 (60 mg).

Tolebrutinib had excellent safety and tolerability in patients with highly active disease and in the overall population, said Dr. Traboulsee.

No adverse events were linked to the study drug. One patient with highly active disease who received 60 mg of tolebrutinib had transient elevated ALT levels greater than three times the upper limit of normal. This patient also previously had elevated ALT at baseline.

One serious adverse event occurred during the study. One patient was hospitalized for MS relapse. The patient had been assigned to the 60-mg dose of tolebrutinib. The patient recovered and remained on study treatment.

Two independent studies have indicated that BTK inhibition is an effective treatment approach for relapsing remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.

“Most, if not all, MS therapies mostly affect the peripheral immune system, preventing autoreactive lymphocytes crossing the blood-brain barrier and causing damage,” said Dr. Traboulsee.

Therapies that enter the CNS can target abnormal immune cells, including microglia that are believed to promote disease progression. “If this is an important target, then we now have a highly CNS-penetrant drug that could potentially change the course of progression,” said Dr. Traboulsee.

Serum biomarkers and advanced imaging data collected during the phase 2 trial could help clarify the mechanisms of disease progression and the effects of tolebrutinib, he added. “Ultimately though, it is the clinical outcomes in the phase 3 programs that are essential to know where to place tolebrutinib in the future care of relapsing and progressive forms of MS.”
 

Not an unmet need

Commenting on the findings, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania, Philadelphia, said there are several available treatments that effectively suppress clinical and radiologic evidence of acute inflammation in relapsing remitting MS.

“Any new drug that is to be added to that pharmacological armamentarium should have distinct advantages over what is currently available. Treating relapsing remitting MS is not, in my opinion, an unmet need in MS; treating progressive disease is,” he said.

Dr. Berger said that tolebrutinib appears to be better than placebo in suppressing disease activity, particularly at higher doses. “However, the study is small – only 61 patients,” noted Dr. Berger, who was not involved in the study.

In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.

“As there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib needs to be tempered with that in mind,” said Dr. Berger.

Evaluating how tolebrutinib compares with other BTK inhibitors will require a head-to-head trial. “I’d be more interested in whether the drug has an effect on progressive disease,” Dr. Berger concluded.

The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Dr. Traboulsee has received research grant support, honoraria for consulting, and honoraria for participating in a speakers’ bureau from Sanofi Genzyme. Dr. Berger disclosed no relevant financial relationships.

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

When it comes to SARS-CoV-2 infection among patients with multiple sclerosis (MS), disease-modifying therapies (DMTs) seem to have varying effects on risk of worse outcomes, according to a new analysis of an Italian cohort of patients with MS. The study confirmed that steroid exposure in the month before COVID-19 symptom onset is tied to more severe disease, and anti-CD20 therapy poses similar risks. But the researchers noted that interferon and possibly teriflunomide were associated with a protective effect in the multivariate analysis.

Maria Pia Sormani, PhD, who is a professor of biostatistics at the University of Genoa, presented the study at the 2021 annual meeting of the American Academy of Neurology.

The results confirm some previous analyses, and add to the body of evidence clinicians rely on, according to Jiwon Oh, MD, PhD, who moderated the session. “These data about the risk with the anti-CD20 therapies have been around for a while, but it seems that risk is pretty apparent, with this registry and other registries around the world. It affects counseling to patients on anti-CD20 therapies. We would counsel them to be cautious, obviously, follow public health precautions, but maybe be even more cautious. It affects our recommendations about the urgency of vaccination in these folks, how high priority they should be,” Dr. Oh said in an interview. She is the clinical director of the Barlo MS Center at St. Michael’s Unity Health in Toronto.

The analysis also hinted at complexities within demographics that might help explain some of the differing outcomes of infections. “We have learned that the course of the viral infection per se may not be the cause of severe outcomes, but the exaggerated inflammatory response to the virus is mainly responsible for intubations and deaths. The hypothesis we are investigating is whether anti-CD20 therapies can cause a more severe viral infection (that is something already known for other viral infections) but do not play a crucial role in causing the explosion of the inflammatory process,” said Dr. Sormani in an email.

The group plans to look at the risk of anti-CD20 therapies in different age groups, “to try to understand the underlying mechanism through which anti-CD20 increases the risk of more severe outcome,” she said.

Dr. Sormani presented an analysis of 3,274 patients with MS who contracted COVID-19 in Italy. The mean age was 44, the median Expanded Disability Status Scale (EDSS) score was 2, Among the study cohort, 68.6% were female; 14% had progressive MS and 26 patients died. Patients who died had a mean age of 63, 48% were female, 73% had progressive MS, and 50% were not on any DMT.

The researchers used ordinal logistic regression that “orders” outcome on a severity scale of 0 (mild disease, no pneumonia or hospitalization), 1 (pneumonia or hospitalization, n = 184), or 2 (ICU admission or death, n = 36). They calculated the odds ratio of moving from 0 to 1, or 1 to 2, and carried the assumption that the risk is the same. For example, an odds ratio of 2 for males versus females would mean that males are twice as likely to be hospitalized and twice as likely to go from being hospitalized to going to the ICU or dying.

The researchers found that older age, male sex, and comorbidities increase risk of worse COVID-19 outcomes. Exposure to methylprednisolone 1 month before COVID-19 symptom onset carried an increased risk (OR, 2.33; P = .03). Compared with no therapy, receiving interferon was associated with lower risk (OR, 0.34; P = .009) and teriflunomide trended towards an association with better outcomes (OR, 0.49; P = .054). Anti-CD20 treatment (ocrelizumab or rituximab) was linked to worse outcomes (OR, 1.89; P = .012) overall, which held up when ocrelizumab (OR, 1.71; P = .04) and rituximab (OR, 2.77; P = .03) were considered separately.

To understand why the risk of ocrelizumab might be lower, the researchers examined risk by duration of anti-CD20 treatment, and found that risk increased with increased duration of treatment, with the lowest risk at treatment duration less than 6 months (OR, 1.56; 95% CI, 0.65-3.77; not significant), followed by 6 months to 1 year (OR, 1.68; 95% CI, 0.69-4.03; P < .001), 1-2 years (OR, 1.74; 95% CI, 0.83-3.64; trend), and the highest risk at more than 2 years (OR, 2.75; 95% CI, 1.28-5.88).

Dr. Sormani suggested that the greater risk associated with rituximab may be because of a tendency towards longer treatment length, since patients treated with rituximab were more often treated for greater lengths of time; 11% had been treated for 6 months or less (vs. 24% of ocrelizumab patients); 26%, 6-12 months (vs. 18% ocrelizumab); 19%, 1-2 years (vs. 37% ocrelizumab); and 44%, 2 years or longer (vs. 21% ocrelizumab).

Dr. Sormani has received consulting fees from Biogen, GeNeuro, Genzyme, MedDay, Merck KGaA, Novartis, Roche, and Immunic. The platform for data collection was donated by Merck. Dr. Oh has consulted for Roche, Celgene, Biogen-Idec, EMD-Serono, Sanofi-Genzyme, Novartis, Alexion. She has been on a scientific advisory or data safety monitoring board for Roche, Biogen-Idec, and Sanofi-Genzyme.

When it comes to SARS-CoV-2 infection among patients with multiple sclerosis (MS), disease-modifying therapies (DMTs) seem to have varying effects on risk of worse outcomes, according to a new analysis of an Italian cohort of patients with MS. The study confirmed that steroid exposure in the month before COVID-19 symptom onset is tied to more severe disease, and anti-CD20 therapy poses similar risks. But the researchers noted that interferon and possibly teriflunomide were associated with a protective effect in the multivariate analysis.

Maria Pia Sormani, PhD, who is a professor of biostatistics at the University of Genoa, presented the study at the 2021 annual meeting of the American Academy of Neurology.

The results confirm some previous analyses, and add to the body of evidence clinicians rely on, according to Jiwon Oh, MD, PhD, who moderated the session. “These data about the risk with the anti-CD20 therapies have been around for a while, but it seems that risk is pretty apparent, with this registry and other registries around the world. It affects counseling to patients on anti-CD20 therapies. We would counsel them to be cautious, obviously, follow public health precautions, but maybe be even more cautious. It affects our recommendations about the urgency of vaccination in these folks, how high priority they should be,” Dr. Oh said in an interview. She is the clinical director of the Barlo MS Center at St. Michael’s Unity Health in Toronto.

The analysis also hinted at complexities within demographics that might help explain some of the differing outcomes of infections. “We have learned that the course of the viral infection per se may not be the cause of severe outcomes, but the exaggerated inflammatory response to the virus is mainly responsible for intubations and deaths. The hypothesis we are investigating is whether anti-CD20 therapies can cause a more severe viral infection (that is something already known for other viral infections) but do not play a crucial role in causing the explosion of the inflammatory process,” said Dr. Sormani in an email.

The group plans to look at the risk of anti-CD20 therapies in different age groups, “to try to understand the underlying mechanism through which anti-CD20 increases the risk of more severe outcome,” she said.

Dr. Sormani presented an analysis of 3,274 patients with MS who contracted COVID-19 in Italy. The mean age was 44, the median Expanded Disability Status Scale (EDSS) score was 2, Among the study cohort, 68.6% were female; 14% had progressive MS and 26 patients died. Patients who died had a mean age of 63, 48% were female, 73% had progressive MS, and 50% were not on any DMT.

The researchers used ordinal logistic regression that “orders” outcome on a severity scale of 0 (mild disease, no pneumonia or hospitalization), 1 (pneumonia or hospitalization, n = 184), or 2 (ICU admission or death, n = 36). They calculated the odds ratio of moving from 0 to 1, or 1 to 2, and carried the assumption that the risk is the same. For example, an odds ratio of 2 for males versus females would mean that males are twice as likely to be hospitalized and twice as likely to go from being hospitalized to going to the ICU or dying.

The researchers found that older age, male sex, and comorbidities increase risk of worse COVID-19 outcomes. Exposure to methylprednisolone 1 month before COVID-19 symptom onset carried an increased risk (OR, 2.33; P = .03). Compared with no therapy, receiving interferon was associated with lower risk (OR, 0.34; P = .009) and teriflunomide trended towards an association with better outcomes (OR, 0.49; P = .054). Anti-CD20 treatment (ocrelizumab or rituximab) was linked to worse outcomes (OR, 1.89; P = .012) overall, which held up when ocrelizumab (OR, 1.71; P = .04) and rituximab (OR, 2.77; P = .03) were considered separately.

To understand why the risk of ocrelizumab might be lower, the researchers examined risk by duration of anti-CD20 treatment, and found that risk increased with increased duration of treatment, with the lowest risk at treatment duration less than 6 months (OR, 1.56; 95% CI, 0.65-3.77; not significant), followed by 6 months to 1 year (OR, 1.68; 95% CI, 0.69-4.03; P < .001), 1-2 years (OR, 1.74; 95% CI, 0.83-3.64; trend), and the highest risk at more than 2 years (OR, 2.75; 95% CI, 1.28-5.88).

Dr. Sormani suggested that the greater risk associated with rituximab may be because of a tendency towards longer treatment length, since patients treated with rituximab were more often treated for greater lengths of time; 11% had been treated for 6 months or less (vs. 24% of ocrelizumab patients); 26%, 6-12 months (vs. 18% ocrelizumab); 19%, 1-2 years (vs. 37% ocrelizumab); and 44%, 2 years or longer (vs. 21% ocrelizumab).

Dr. Sormani has received consulting fees from Biogen, GeNeuro, Genzyme, MedDay, Merck KGaA, Novartis, Roche, and Immunic. The platform for data collection was donated by Merck. Dr. Oh has consulted for Roche, Celgene, Biogen-Idec, EMD-Serono, Sanofi-Genzyme, Novartis, Alexion. She has been on a scientific advisory or data safety monitoring board for Roche, Biogen-Idec, and Sanofi-Genzyme.

When it comes to SARS-CoV-2 infection among patients with multiple sclerosis (MS), disease-modifying therapies (DMTs) seem to have varying effects on risk of worse outcomes, according to a new analysis of an Italian cohort of patients with MS. The study confirmed that steroid exposure in the month before COVID-19 symptom onset is tied to more severe disease, and anti-CD20 therapy poses similar risks. But the researchers noted that interferon and possibly teriflunomide were associated with a protective effect in the multivariate analysis.

Maria Pia Sormani, PhD, who is a professor of biostatistics at the University of Genoa, presented the study at the 2021 annual meeting of the American Academy of Neurology.

The results confirm some previous analyses, and add to the body of evidence clinicians rely on, according to Jiwon Oh, MD, PhD, who moderated the session. “These data about the risk with the anti-CD20 therapies have been around for a while, but it seems that risk is pretty apparent, with this registry and other registries around the world. It affects counseling to patients on anti-CD20 therapies. We would counsel them to be cautious, obviously, follow public health precautions, but maybe be even more cautious. It affects our recommendations about the urgency of vaccination in these folks, how high priority they should be,” Dr. Oh said in an interview. She is the clinical director of the Barlo MS Center at St. Michael’s Unity Health in Toronto.

The analysis also hinted at complexities within demographics that might help explain some of the differing outcomes of infections. “We have learned that the course of the viral infection per se may not be the cause of severe outcomes, but the exaggerated inflammatory response to the virus is mainly responsible for intubations and deaths. The hypothesis we are investigating is whether anti-CD20 therapies can cause a more severe viral infection (that is something already known for other viral infections) but do not play a crucial role in causing the explosion of the inflammatory process,” said Dr. Sormani in an email.

The group plans to look at the risk of anti-CD20 therapies in different age groups, “to try to understand the underlying mechanism through which anti-CD20 increases the risk of more severe outcome,” she said.

Dr. Sormani presented an analysis of 3,274 patients with MS who contracted COVID-19 in Italy. The mean age was 44, the median Expanded Disability Status Scale (EDSS) score was 2, Among the study cohort, 68.6% were female; 14% had progressive MS and 26 patients died. Patients who died had a mean age of 63, 48% were female, 73% had progressive MS, and 50% were not on any DMT.

The researchers used ordinal logistic regression that “orders” outcome on a severity scale of 0 (mild disease, no pneumonia or hospitalization), 1 (pneumonia or hospitalization, n = 184), or 2 (ICU admission or death, n = 36). They calculated the odds ratio of moving from 0 to 1, or 1 to 2, and carried the assumption that the risk is the same. For example, an odds ratio of 2 for males versus females would mean that males are twice as likely to be hospitalized and twice as likely to go from being hospitalized to going to the ICU or dying.

The researchers found that older age, male sex, and comorbidities increase risk of worse COVID-19 outcomes. Exposure to methylprednisolone 1 month before COVID-19 symptom onset carried an increased risk (OR, 2.33; P = .03). Compared with no therapy, receiving interferon was associated with lower risk (OR, 0.34; P = .009) and teriflunomide trended towards an association with better outcomes (OR, 0.49; P = .054). Anti-CD20 treatment (ocrelizumab or rituximab) was linked to worse outcomes (OR, 1.89; P = .012) overall, which held up when ocrelizumab (OR, 1.71; P = .04) and rituximab (OR, 2.77; P = .03) were considered separately.

To understand why the risk of ocrelizumab might be lower, the researchers examined risk by duration of anti-CD20 treatment, and found that risk increased with increased duration of treatment, with the lowest risk at treatment duration less than 6 months (OR, 1.56; 95% CI, 0.65-3.77; not significant), followed by 6 months to 1 year (OR, 1.68; 95% CI, 0.69-4.03; P < .001), 1-2 years (OR, 1.74; 95% CI, 0.83-3.64; trend), and the highest risk at more than 2 years (OR, 2.75; 95% CI, 1.28-5.88).

Dr. Sormani suggested that the greater risk associated with rituximab may be because of a tendency towards longer treatment length, since patients treated with rituximab were more often treated for greater lengths of time; 11% had been treated for 6 months or less (vs. 24% of ocrelizumab patients); 26%, 6-12 months (vs. 18% ocrelizumab); 19%, 1-2 years (vs. 37% ocrelizumab); and 44%, 2 years or longer (vs. 21% ocrelizumab).

Dr. Sormani has received consulting fees from Biogen, GeNeuro, Genzyme, MedDay, Merck KGaA, Novartis, Roche, and Immunic. The platform for data collection was donated by Merck. Dr. Oh has consulted for Roche, Celgene, Biogen-Idec, EMD-Serono, Sanofi-Genzyme, Novartis, Alexion. She has been on a scientific advisory or data safety monitoring board for Roche, Biogen-Idec, and Sanofi-Genzyme.

Vagus nerve stimulation (VNS) paired with intensive rehabilitation for moderate to severe arm weakness months or even years after stroke may lead to a greater improvement in arm function than rehabilitation alone, according to preliminary results of a randomized clinical trial at the 2021 annual meeting of the American Academy of Neurology.

“We believe that vagus nerve stimulation combined with rehabilitation is an acceptable and effective intervention for improving upper-limb impairment and function in people with moderate to severe arm weakness a long time VNS-REHAB pivotal study is a randomized, blinded, controlled trial of 108 people who had upper-extremity weakness after having a stroke at least 9 months before enrollment. The average for the group was 3 years post stroke after ischemic stroke,” said Jesse Dawson, MD, a professor at the University of Glasgow.

The Fifty-three patients were assigned active VNS followed by 6 weeks of in-clinic rehabilitation and then 90 days of home-based rehab. At in-clinic rehab, the therapist initiated a 5-second burst of VNS stimulation during each movement. In home-base treatment, the device was activated by a magnet.

Fifty-five patients were assigned sham VNS. After 90 days, the sham group crossed over to receive VNS for 6 weeks and then 90 days of home exercise. This crossover group was the focus of the data Dr. Dawson presented at AAN 2021. The overall trial results have been published in the Lancet.

“The hypothesis is based on the knowledge that the VNS stimulates the release of proneuroplastic neuromodulators norepinephrine and acetylcholine,” Dr. Dawson said. “By pairing VNS with task-specific movement, we hypothesize that we will increase task-specific neuroplasticity.”

The main study showed “a statistically significant difference across all primary and secondary endpoints at all time points in favor of rehabilitation paired with VNS,” Dr. Dawson said. The primary outcome was improvement in Fugl-Meyer Upper Extremity (FMA-UE) outcome, with the active VNS group having a significantly higher percentage of responders. For example, 47% of the active VNS patients had a greater than 6-point response on FMA-UE improvement versus 27% of the sham group (P = .010).

When the sham group crossed over to active VNS, the improvement in arm function matched that of the treatment group in the main study, Dr. Dawson said. “If you look at specifically what happened after they completed the control phase, there was a further small increase in Fugl-Meyer score, but, more importantly between 20% and 35% achieved a clinically important response on the Fugl-Meyer assessment or the Wolf Motor Function Test, giving a number need to treat ranging from three to five,” he said.

Dr. Dawson said that data on adverse events was presented in the Lancet publication. “These were observed at expected frequencies,” he said.

In an interview, he explained the significance of reporting the number to treat. “The number needed to treat helps give an idea of how many times you need to do something to achieve the desired outcome. So for VNS paired with rehab versus rehab alone, you need to treat four people to get one extra clinically important response, compared with just doing therapy.”

The next steps for his group’s research, he said, “will be to try and explore whether we can predict who responds best, and we would like to see if people with other types of stroke benefit.”

In providing comment on the study, Andreas Luft, MD, a professor at the University Hospital Zürich, noted that the FME-UE score improvements reported “are significant and meaningful. ... However, they may also be achieved by increasing the intensity of training. Many medical systems offer their patients high rehabilitation intensities and achieve similar improvements. Whether VNS can further boost higher-intensity training ‘beyond its limits’ is probable but remains to be demonstrated.”

Dr. Luft noted the study advances the knowledge of combining a therapeutic approach with training. “More such approaches are necessary to increase the therapeutic instrumentation of neurorehabilitation,” he said.

Dr. Dawson reported a financial relationship with MicroTransponder. His coauthors reported relationships with MicroTransponder, SanBio, Fujifilm Toyoma Chemical, Medtronic, TRCare, SAEBO, Allergan/AbbVie, Ipsen, Merz, Ottobock/Hangar Orthopedics, Parker Hannifin, Revance Therapeutics, ReWallk, and Sword Health. Three coauthors are employees of MicroTransponder. Dr. Luft has no relevant relationships to disclose.

Vagus nerve stimulation (VNS) paired with intensive rehabilitation for moderate to severe arm weakness months or even years after stroke may lead to a greater improvement in arm function than rehabilitation alone, according to preliminary results of a randomized clinical trial at the 2021 annual meeting of the American Academy of Neurology.

“We believe that vagus nerve stimulation combined with rehabilitation is an acceptable and effective intervention for improving upper-limb impairment and function in people with moderate to severe arm weakness a long time VNS-REHAB pivotal study is a randomized, blinded, controlled trial of 108 people who had upper-extremity weakness after having a stroke at least 9 months before enrollment. The average for the group was 3 years post stroke after ischemic stroke,” said Jesse Dawson, MD, a professor at the University of Glasgow.

The Fifty-three patients were assigned active VNS followed by 6 weeks of in-clinic rehabilitation and then 90 days of home-based rehab. At in-clinic rehab, the therapist initiated a 5-second burst of VNS stimulation during each movement. In home-base treatment, the device was activated by a magnet.

Fifty-five patients were assigned sham VNS. After 90 days, the sham group crossed over to receive VNS for 6 weeks and then 90 days of home exercise. This crossover group was the focus of the data Dr. Dawson presented at AAN 2021. The overall trial results have been published in the Lancet.

“The hypothesis is based on the knowledge that the VNS stimulates the release of proneuroplastic neuromodulators norepinephrine and acetylcholine,” Dr. Dawson said. “By pairing VNS with task-specific movement, we hypothesize that we will increase task-specific neuroplasticity.”

The main study showed “a statistically significant difference across all primary and secondary endpoints at all time points in favor of rehabilitation paired with VNS,” Dr. Dawson said. The primary outcome was improvement in Fugl-Meyer Upper Extremity (FMA-UE) outcome, with the active VNS group having a significantly higher percentage of responders. For example, 47% of the active VNS patients had a greater than 6-point response on FMA-UE improvement versus 27% of the sham group (P = .010).

When the sham group crossed over to active VNS, the improvement in arm function matched that of the treatment group in the main study, Dr. Dawson said. “If you look at specifically what happened after they completed the control phase, there was a further small increase in Fugl-Meyer score, but, more importantly between 20% and 35% achieved a clinically important response on the Fugl-Meyer assessment or the Wolf Motor Function Test, giving a number need to treat ranging from three to five,” he said.

Dr. Dawson said that data on adverse events was presented in the Lancet publication. “These were observed at expected frequencies,” he said.

In an interview, he explained the significance of reporting the number to treat. “The number needed to treat helps give an idea of how many times you need to do something to achieve the desired outcome. So for VNS paired with rehab versus rehab alone, you need to treat four people to get one extra clinically important response, compared with just doing therapy.”

The next steps for his group’s research, he said, “will be to try and explore whether we can predict who responds best, and we would like to see if people with other types of stroke benefit.”

In providing comment on the study, Andreas Luft, MD, a professor at the University Hospital Zürich, noted that the FME-UE score improvements reported “are significant and meaningful. ... However, they may also be achieved by increasing the intensity of training. Many medical systems offer their patients high rehabilitation intensities and achieve similar improvements. Whether VNS can further boost higher-intensity training ‘beyond its limits’ is probable but remains to be demonstrated.”

Dr. Luft noted the study advances the knowledge of combining a therapeutic approach with training. “More such approaches are necessary to increase the therapeutic instrumentation of neurorehabilitation,” he said.

Dr. Dawson reported a financial relationship with MicroTransponder. His coauthors reported relationships with MicroTransponder, SanBio, Fujifilm Toyoma Chemical, Medtronic, TRCare, SAEBO, Allergan/AbbVie, Ipsen, Merz, Ottobock/Hangar Orthopedics, Parker Hannifin, Revance Therapeutics, ReWallk, and Sword Health. Three coauthors are employees of MicroTransponder. Dr. Luft has no relevant relationships to disclose.

Vagus nerve stimulation (VNS) paired with intensive rehabilitation for moderate to severe arm weakness months or even years after stroke may lead to a greater improvement in arm function than rehabilitation alone, according to preliminary results of a randomized clinical trial at the 2021 annual meeting of the American Academy of Neurology.

“We believe that vagus nerve stimulation combined with rehabilitation is an acceptable and effective intervention for improving upper-limb impairment and function in people with moderate to severe arm weakness a long time VNS-REHAB pivotal study is a randomized, blinded, controlled trial of 108 people who had upper-extremity weakness after having a stroke at least 9 months before enrollment. The average for the group was 3 years post stroke after ischemic stroke,” said Jesse Dawson, MD, a professor at the University of Glasgow.

The Fifty-three patients were assigned active VNS followed by 6 weeks of in-clinic rehabilitation and then 90 days of home-based rehab. At in-clinic rehab, the therapist initiated a 5-second burst of VNS stimulation during each movement. In home-base treatment, the device was activated by a magnet.

Fifty-five patients were assigned sham VNS. After 90 days, the sham group crossed over to receive VNS for 6 weeks and then 90 days of home exercise. This crossover group was the focus of the data Dr. Dawson presented at AAN 2021. The overall trial results have been published in the Lancet.

“The hypothesis is based on the knowledge that the VNS stimulates the release of proneuroplastic neuromodulators norepinephrine and acetylcholine,” Dr. Dawson said. “By pairing VNS with task-specific movement, we hypothesize that we will increase task-specific neuroplasticity.”

The main study showed “a statistically significant difference across all primary and secondary endpoints at all time points in favor of rehabilitation paired with VNS,” Dr. Dawson said. The primary outcome was improvement in Fugl-Meyer Upper Extremity (FMA-UE) outcome, with the active VNS group having a significantly higher percentage of responders. For example, 47% of the active VNS patients had a greater than 6-point response on FMA-UE improvement versus 27% of the sham group (P = .010).

When the sham group crossed over to active VNS, the improvement in arm function matched that of the treatment group in the main study, Dr. Dawson said. “If you look at specifically what happened after they completed the control phase, there was a further small increase in Fugl-Meyer score, but, more importantly between 20% and 35% achieved a clinically important response on the Fugl-Meyer assessment or the Wolf Motor Function Test, giving a number need to treat ranging from three to five,” he said.

Dr. Dawson said that data on adverse events was presented in the Lancet publication. “These were observed at expected frequencies,” he said.

In an interview, he explained the significance of reporting the number to treat. “The number needed to treat helps give an idea of how many times you need to do something to achieve the desired outcome. So for VNS paired with rehab versus rehab alone, you need to treat four people to get one extra clinically important response, compared with just doing therapy.”

The next steps for his group’s research, he said, “will be to try and explore whether we can predict who responds best, and we would like to see if people with other types of stroke benefit.”

In providing comment on the study, Andreas Luft, MD, a professor at the University Hospital Zürich, noted that the FME-UE score improvements reported “are significant and meaningful. ... However, they may also be achieved by increasing the intensity of training. Many medical systems offer their patients high rehabilitation intensities and achieve similar improvements. Whether VNS can further boost higher-intensity training ‘beyond its limits’ is probable but remains to be demonstrated.”

Dr. Luft noted the study advances the knowledge of combining a therapeutic approach with training. “More such approaches are necessary to increase the therapeutic instrumentation of neurorehabilitation,” he said.

Dr. Dawson reported a financial relationship with MicroTransponder. His coauthors reported relationships with MicroTransponder, SanBio, Fujifilm Toyoma Chemical, Medtronic, TRCare, SAEBO, Allergan/AbbVie, Ipsen, Merz, Ottobock/Hangar Orthopedics, Parker Hannifin, Revance Therapeutics, ReWallk, and Sword Health. Three coauthors are employees of MicroTransponder. Dr. Luft has no relevant relationships to disclose.

Further evidence supporting the safety of two antiseizure medications in pregnancy has come from a new study. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study found no difference in neurobehavioral development in children at age 3 born to women with epilepsy compared with children of healthy women without epilepsy. Most of the women with epilepsy in the study took either lamotrigine or levetiracetam, or a combination of the two, during their pregnancy.

However, a secondary analysis suggested a possible signal of exposure-dependent effects on child outcomes – worse outcomes with higher exposure levels – with levetiracetam.

The results were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Additional reassurance

“Our new study adds confidence to the use of lamotrigine and levetiracetam during pregnancy, adding larger numbers with a new cohort. In addition, it provides some preliminary data on some of the other new antiseizure medications, and it is the first study to address the effects of clearance in pregnancy to better assess exposure,” said lead investigator, Kimford J. Meador, MD. “Overall, I am reassured by this data, but there is still a lot that is unknown,” he added.

“Our main results show no difference in verbal index or general conceptual ability scores in children born to women with epilepsy compared to children born to healthy women. This is a big positive message,” Dr. Meador said.   

In terms of secondary analysis focusing on exposure levels (dose and blood levels of antiseizure medications), there was no overall signal of harm when looking at the whole group, but when the researchers analyzed the data on individual drugs, they found a “slight signal” toward reduced verbal index scores with increasing exposure levels with levetiracetam. No differences were seen on general conceptual ability. 

“In the secondary analysis, there was a marginal signal for exposure levels with levetiracetam, with increased blood levels of the drug associated with reduced verbal index scores,” reported Dr. Meador, professor of neurology and neurological sciences at Stanford (Calif.) University. “We saw some signal in the children when they were 2 years old, and this was still there but not as striking at 3 years old.” 

He said these secondary results should be interpreted with extreme caution. “We don’t want to overemphasize these secondary findings, as the primary outcome showed no difference, and there was no effect on exposure levels when looking at all the drugs together. I don’t want to oversimplify this, as I am still not sure whether this is a real association or not,” Dr. Meador commented.

He explained that conducting neurobehavioral tests on 2- and 3-year-olds was very difficult. “It is more of an art form than science, and as the children get older these signals often dissipate. We will know more by the time they are 6, when these tests become easier to conduct,” he said. He also noted that the results would need to be replicated in a different cohort.

“I don’t think these results would change how we manage women during pregnancy in terms of using levetiracetam. It is still a safe drug during pregnancy,” Dr. Meador said.

He pointed out that data on safety in pregnancy is only available for very few antiseizure drugs. “There are over 30 antiseizure medications, but we have adequate data in pregnancy on only a handful. We have data suggesting lamotrigine, levetiracetam, and carbamazepine appear to be relatively safe, and evidence showing phenobarbital and valproate are not safe.”

Antiseizure medications as a class are among the most commonly prescribed teratogenic drugs given to women of childbearing age, Dr. Meador noted. They are used not only for epilepsy but also for many other psychiatric and pain indications, so these results are applicable to quite a broad population, he added.

He pointed out that previous studies did not assess exposure using blood levels, which is important, as clearance of drug increases during pregnancy but varies across antiseizure medications and across individuals on the same drug. “Thus, it is unclear if these changes could obscure exposure-dependent effects. Our present studies assessed blood levels to better measure fetal exposure.”
 

Advice for pregnant patients with epilepsy

Dr. Meador explained that risk for adverse effects with antiseizure medication always needs to be balanced with risk for seizures if the medication was not used.

“In women planning a pregnancy, we recommend that they plan ahead with their physician to try and use the safest antiseizure medication and gain good control beforehand and then maintain the same blood levels of whichever drug is being used during pregnancy,” Dr. Meador said. “At present, lamotrigine and levetiracetam are the two safest drugs to use in pregnancy. They both look generally very safe compared with some other epilepsy drugs – such as valproate, which poses a serious risk to cognitive and behavioral development.” 

He also advised that women should be taking folic acid regularly, as this has been shown to be related to improved cognitive and behavioral outcomes. “Since half of pregnancies are not planned, it is important to take these actions before pregnancy,” he added.

The current study involved 289 women with epilepsy and 89 women without epilepsy, all of whom enrolled in the study during pregnancy. Use of antiseizure medications was recorded. Of the women with epilepsy, 74% were on monotherapy, with 43% on lamotrigine and 37% on levetiracetam. There were 4% who took no drug and 22% took more than one drug. Of those who took more than one drug, close to half took a combination of lamotrigine and levetiracetam. Levels of medications in the blood of the women with epilepsy were measured in the third trimester.
 

Assessment of neurobehavioral development

For the current analysis, the children were evaluated at age 3 with a series of cognitive and developmental tests that measured vocabulary, listening comprehension, number recall, and pattern recognition, and results were adjusted for mother’s IQ, education level, age at enrollment, postbirth average BAI (Beck Anxiety Inventory score), and child’s ethnicity, sex, and breastfeeding status.

The primary outcome showed that verbal Index scores at age 3 did not differ for children of women with epilepsy versus those for children of women without epilepsy (LS mean 102.7 vs. 102.1).

Antiseizure medication exposure as evident by the maximum third trimester blood levels was not related to verbal index scores (n = 265; adjusted parameter estimate, -1.9; 95% confidence interval, -6.8 to 3.1).

General conceptual ability scores also did not differ between the two groups: 105.1 for children of women with epilepsy versus 103.5 for children of healthy women.

In terms of exposure levels, the third trimester maximum observed ratio of antiseizure medication blood levels was not significantly associated with adjusted general conceptual ability scores for children of women with epilepsy; neither were monotherapies or polytherapies evaluated separately, Dr. Meador reported.

However, when the verbal index scores for the main antiepileptic drug groups were analyzed separately, exposure level to levetiracetam was the only one that was significant, with a P value of .028. But Dr. Meador again stressed that this finding should be interpreted with caution given that it is a secondary exploratory analysis without control for multiple comparisons.

The researchers plan to assess these children at older ages where evaluations are more sensitive to ultimate outcomes.

“Information on use in pregnancy for most antiseizure medications is still unknown, so further studies to assess risks for the newer antiseizure medications are needed,” Dr. Meador added. “Further, additional research is needed on the underlying mechanisms including genetic predispositions, since teratogens act on a susceptible genotype.”

The study was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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

Further evidence supporting the safety of two antiseizure medications in pregnancy has come from a new study. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study found no difference in neurobehavioral development in children at age 3 born to women with epilepsy compared with children of healthy women without epilepsy. Most of the women with epilepsy in the study took either lamotrigine or levetiracetam, or a combination of the two, during their pregnancy.

However, a secondary analysis suggested a possible signal of exposure-dependent effects on child outcomes – worse outcomes with higher exposure levels – with levetiracetam.

The results were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Additional reassurance

“Our new study adds confidence to the use of lamotrigine and levetiracetam during pregnancy, adding larger numbers with a new cohort. In addition, it provides some preliminary data on some of the other new antiseizure medications, and it is the first study to address the effects of clearance in pregnancy to better assess exposure,” said lead investigator, Kimford J. Meador, MD. “Overall, I am reassured by this data, but there is still a lot that is unknown,” he added.

“Our main results show no difference in verbal index or general conceptual ability scores in children born to women with epilepsy compared to children born to healthy women. This is a big positive message,” Dr. Meador said.   

In terms of secondary analysis focusing on exposure levels (dose and blood levels of antiseizure medications), there was no overall signal of harm when looking at the whole group, but when the researchers analyzed the data on individual drugs, they found a “slight signal” toward reduced verbal index scores with increasing exposure levels with levetiracetam. No differences were seen on general conceptual ability. 

“In the secondary analysis, there was a marginal signal for exposure levels with levetiracetam, with increased blood levels of the drug associated with reduced verbal index scores,” reported Dr. Meador, professor of neurology and neurological sciences at Stanford (Calif.) University. “We saw some signal in the children when they were 2 years old, and this was still there but not as striking at 3 years old.” 

He said these secondary results should be interpreted with extreme caution. “We don’t want to overemphasize these secondary findings, as the primary outcome showed no difference, and there was no effect on exposure levels when looking at all the drugs together. I don’t want to oversimplify this, as I am still not sure whether this is a real association or not,” Dr. Meador commented.

He explained that conducting neurobehavioral tests on 2- and 3-year-olds was very difficult. “It is more of an art form than science, and as the children get older these signals often dissipate. We will know more by the time they are 6, when these tests become easier to conduct,” he said. He also noted that the results would need to be replicated in a different cohort.

“I don’t think these results would change how we manage women during pregnancy in terms of using levetiracetam. It is still a safe drug during pregnancy,” Dr. Meador said.

He pointed out that data on safety in pregnancy is only available for very few antiseizure drugs. “There are over 30 antiseizure medications, but we have adequate data in pregnancy on only a handful. We have data suggesting lamotrigine, levetiracetam, and carbamazepine appear to be relatively safe, and evidence showing phenobarbital and valproate are not safe.”

Antiseizure medications as a class are among the most commonly prescribed teratogenic drugs given to women of childbearing age, Dr. Meador noted. They are used not only for epilepsy but also for many other psychiatric and pain indications, so these results are applicable to quite a broad population, he added.

He pointed out that previous studies did not assess exposure using blood levels, which is important, as clearance of drug increases during pregnancy but varies across antiseizure medications and across individuals on the same drug. “Thus, it is unclear if these changes could obscure exposure-dependent effects. Our present studies assessed blood levels to better measure fetal exposure.”
 

Advice for pregnant patients with epilepsy

Dr. Meador explained that risk for adverse effects with antiseizure medication always needs to be balanced with risk for seizures if the medication was not used.

“In women planning a pregnancy, we recommend that they plan ahead with their physician to try and use the safest antiseizure medication and gain good control beforehand and then maintain the same blood levels of whichever drug is being used during pregnancy,” Dr. Meador said. “At present, lamotrigine and levetiracetam are the two safest drugs to use in pregnancy. They both look generally very safe compared with some other epilepsy drugs – such as valproate, which poses a serious risk to cognitive and behavioral development.” 

He also advised that women should be taking folic acid regularly, as this has been shown to be related to improved cognitive and behavioral outcomes. “Since half of pregnancies are not planned, it is important to take these actions before pregnancy,” he added.

The current study involved 289 women with epilepsy and 89 women without epilepsy, all of whom enrolled in the study during pregnancy. Use of antiseizure medications was recorded. Of the women with epilepsy, 74% were on monotherapy, with 43% on lamotrigine and 37% on levetiracetam. There were 4% who took no drug and 22% took more than one drug. Of those who took more than one drug, close to half took a combination of lamotrigine and levetiracetam. Levels of medications in the blood of the women with epilepsy were measured in the third trimester.
 

Assessment of neurobehavioral development

For the current analysis, the children were evaluated at age 3 with a series of cognitive and developmental tests that measured vocabulary, listening comprehension, number recall, and pattern recognition, and results were adjusted for mother’s IQ, education level, age at enrollment, postbirth average BAI (Beck Anxiety Inventory score), and child’s ethnicity, sex, and breastfeeding status.

The primary outcome showed that verbal Index scores at age 3 did not differ for children of women with epilepsy versus those for children of women without epilepsy (LS mean 102.7 vs. 102.1).

Antiseizure medication exposure as evident by the maximum third trimester blood levels was not related to verbal index scores (n = 265; adjusted parameter estimate, -1.9; 95% confidence interval, -6.8 to 3.1).

General conceptual ability scores also did not differ between the two groups: 105.1 for children of women with epilepsy versus 103.5 for children of healthy women.

In terms of exposure levels, the third trimester maximum observed ratio of antiseizure medication blood levels was not significantly associated with adjusted general conceptual ability scores for children of women with epilepsy; neither were monotherapies or polytherapies evaluated separately, Dr. Meador reported.

However, when the verbal index scores for the main antiepileptic drug groups were analyzed separately, exposure level to levetiracetam was the only one that was significant, with a P value of .028. But Dr. Meador again stressed that this finding should be interpreted with caution given that it is a secondary exploratory analysis without control for multiple comparisons.

The researchers plan to assess these children at older ages where evaluations are more sensitive to ultimate outcomes.

“Information on use in pregnancy for most antiseizure medications is still unknown, so further studies to assess risks for the newer antiseizure medications are needed,” Dr. Meador added. “Further, additional research is needed on the underlying mechanisms including genetic predispositions, since teratogens act on a susceptible genotype.”

The study was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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

Further evidence supporting the safety of two antiseizure medications in pregnancy has come from a new study. The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study found no difference in neurobehavioral development in children at age 3 born to women with epilepsy compared with children of healthy women without epilepsy. Most of the women with epilepsy in the study took either lamotrigine or levetiracetam, or a combination of the two, during their pregnancy.

However, a secondary analysis suggested a possible signal of exposure-dependent effects on child outcomes – worse outcomes with higher exposure levels – with levetiracetam.

The results were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Additional reassurance

“Our new study adds confidence to the use of lamotrigine and levetiracetam during pregnancy, adding larger numbers with a new cohort. In addition, it provides some preliminary data on some of the other new antiseizure medications, and it is the first study to address the effects of clearance in pregnancy to better assess exposure,” said lead investigator, Kimford J. Meador, MD. “Overall, I am reassured by this data, but there is still a lot that is unknown,” he added.

“Our main results show no difference in verbal index or general conceptual ability scores in children born to women with epilepsy compared to children born to healthy women. This is a big positive message,” Dr. Meador said.   

In terms of secondary analysis focusing on exposure levels (dose and blood levels of antiseizure medications), there was no overall signal of harm when looking at the whole group, but when the researchers analyzed the data on individual drugs, they found a “slight signal” toward reduced verbal index scores with increasing exposure levels with levetiracetam. No differences were seen on general conceptual ability. 

“In the secondary analysis, there was a marginal signal for exposure levels with levetiracetam, with increased blood levels of the drug associated with reduced verbal index scores,” reported Dr. Meador, professor of neurology and neurological sciences at Stanford (Calif.) University. “We saw some signal in the children when they were 2 years old, and this was still there but not as striking at 3 years old.” 

He said these secondary results should be interpreted with extreme caution. “We don’t want to overemphasize these secondary findings, as the primary outcome showed no difference, and there was no effect on exposure levels when looking at all the drugs together. I don’t want to oversimplify this, as I am still not sure whether this is a real association or not,” Dr. Meador commented.

He explained that conducting neurobehavioral tests on 2- and 3-year-olds was very difficult. “It is more of an art form than science, and as the children get older these signals often dissipate. We will know more by the time they are 6, when these tests become easier to conduct,” he said. He also noted that the results would need to be replicated in a different cohort.

“I don’t think these results would change how we manage women during pregnancy in terms of using levetiracetam. It is still a safe drug during pregnancy,” Dr. Meador said.

He pointed out that data on safety in pregnancy is only available for very few antiseizure drugs. “There are over 30 antiseizure medications, but we have adequate data in pregnancy on only a handful. We have data suggesting lamotrigine, levetiracetam, and carbamazepine appear to be relatively safe, and evidence showing phenobarbital and valproate are not safe.”

Antiseizure medications as a class are among the most commonly prescribed teratogenic drugs given to women of childbearing age, Dr. Meador noted. They are used not only for epilepsy but also for many other psychiatric and pain indications, so these results are applicable to quite a broad population, he added.

He pointed out that previous studies did not assess exposure using blood levels, which is important, as clearance of drug increases during pregnancy but varies across antiseizure medications and across individuals on the same drug. “Thus, it is unclear if these changes could obscure exposure-dependent effects. Our present studies assessed blood levels to better measure fetal exposure.”
 

Advice for pregnant patients with epilepsy

Dr. Meador explained that risk for adverse effects with antiseizure medication always needs to be balanced with risk for seizures if the medication was not used.

“In women planning a pregnancy, we recommend that they plan ahead with their physician to try and use the safest antiseizure medication and gain good control beforehand and then maintain the same blood levels of whichever drug is being used during pregnancy,” Dr. Meador said. “At present, lamotrigine and levetiracetam are the two safest drugs to use in pregnancy. They both look generally very safe compared with some other epilepsy drugs – such as valproate, which poses a serious risk to cognitive and behavioral development.” 

He also advised that women should be taking folic acid regularly, as this has been shown to be related to improved cognitive and behavioral outcomes. “Since half of pregnancies are not planned, it is important to take these actions before pregnancy,” he added.

The current study involved 289 women with epilepsy and 89 women without epilepsy, all of whom enrolled in the study during pregnancy. Use of antiseizure medications was recorded. Of the women with epilepsy, 74% were on monotherapy, with 43% on lamotrigine and 37% on levetiracetam. There were 4% who took no drug and 22% took more than one drug. Of those who took more than one drug, close to half took a combination of lamotrigine and levetiracetam. Levels of medications in the blood of the women with epilepsy were measured in the third trimester.
 

Assessment of neurobehavioral development

For the current analysis, the children were evaluated at age 3 with a series of cognitive and developmental tests that measured vocabulary, listening comprehension, number recall, and pattern recognition, and results were adjusted for mother’s IQ, education level, age at enrollment, postbirth average BAI (Beck Anxiety Inventory score), and child’s ethnicity, sex, and breastfeeding status.

The primary outcome showed that verbal Index scores at age 3 did not differ for children of women with epilepsy versus those for children of women without epilepsy (LS mean 102.7 vs. 102.1).

Antiseizure medication exposure as evident by the maximum third trimester blood levels was not related to verbal index scores (n = 265; adjusted parameter estimate, -1.9; 95% confidence interval, -6.8 to 3.1).

General conceptual ability scores also did not differ between the two groups: 105.1 for children of women with epilepsy versus 103.5 for children of healthy women.

In terms of exposure levels, the third trimester maximum observed ratio of antiseizure medication blood levels was not significantly associated with adjusted general conceptual ability scores for children of women with epilepsy; neither were monotherapies or polytherapies evaluated separately, Dr. Meador reported.

However, when the verbal index scores for the main antiepileptic drug groups were analyzed separately, exposure level to levetiracetam was the only one that was significant, with a P value of .028. But Dr. Meador again stressed that this finding should be interpreted with caution given that it is a secondary exploratory analysis without control for multiple comparisons.

The researchers plan to assess these children at older ages where evaluations are more sensitive to ultimate outcomes.

“Information on use in pregnancy for most antiseizure medications is still unknown, so further studies to assess risks for the newer antiseizure medications are needed,” Dr. Meador added. “Further, additional research is needed on the underlying mechanisms including genetic predispositions, since teratogens act on a susceptible genotype.”

The study was supported by the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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

People with clinically diagnosed depression and anxiety may be prone to developing Alzheimer’s disease at a younger age than other people, and those with a history of posttraumatic stress disorder may be prone to Alzheimer’s disease onset even earlier in life, according to findings from a review of 1,500 patients with Alzheimer’s disease from a single-center population.

“Could psychosis symptoms be the proverbial canary in a coal mine?” Emily Eijansantos, a medical student at the University of California, San Francisco, said in reporting results of the chart review at the 2021 annual meeting of the American Academy of Neurology. “Previously in this cohort it was found that neurodevelopmental factors as well as chronic insults such as autoimmunity and seizure were also associated with an early age of onset in Alzheimer’s disease.”

The link between depression and autoimmunity, and anxiety and seizure “beg more questions about underlying pathophysiology,” she said. The study included 750 patients with early-onset Alzheimer’s disease and a similar number of late-onset patients from the UCSF Memory and Aging Center.
 

An inverse correlation between psychiatric disorders and age of Alzheimer’s onset

In the total study population, 43.5% (n = 652) had a previous diagnosis of depression and 32.3% (n = 485) had been diagnosed with anxiety. That, Ms. Eijansantos said, falls into similar ranges that other studies have reported.

“When we look at individual psychiatric disorders, we find that those with depression, anxiety, or PTSD are younger on average,” she said. “Patients with depression and anxiety are more [likely] female and have less vascular risk factors, and we observed an association between depression and autoimmunity, anxiety, and seizures.”

Specifically, patients with a history of depression were 2.2 years younger, on average, at the age of onset than patients without such history (P = .01); those with anxiety were 3 years younger on average (P = .01); and those with PTSD were 6.8 years younger on average, although only 1% (n = 15) of study subjects had PTSD, making for a small sample to study. These age-of-onset disparities didn’t appear among patients with previously diagnosed bipolar disorder (BPD) or schizophrenia.

Ms. Eijansantos noted that there were no differences in education attained or apolipoprotein-E gene status between the patients with and without a history of psychosis, and, within the subgroups of individual psychiatric disorders, there were no differences between patients with past and current or formal and informal diagnoses.

“When we split the cohort into quintiles based on age of Alzheimer’s disease onset, we find an inverse correlation between the amount of depression, anxiety, and PTSD endorsed and their ages of onset,” Ms. Eijansantos said. For example, the youngest quintile had a greater than 50% rate of depression while the oldest quintile had a depression rate around 36%. A similar spread was found with anxiety: a rate around 46% in the youngest quantile versus around 25% in the oldest, whereas rates of PTSD, BPD, and schizophrenia were similar across the five age-of-onset groups.

Patients with a history of multiple psychiatric disorders had an even younger age of onset. “We see that those with two psychiatric disorder are younger than those with one, and those with three psychiatric disorders are younger still,” Ms. Eijansantos said. “And we find that the Alzheimer’s disease age-at-onset reduction doubles with each additional psychiatric disorder.” Multiple disorders also adversely impacted survival, she said.

Because they found no difference between patients with past versus active symptoms and informal versus formal diagnosis, Ms. Eijansantos explained that they further studied the National Alzheimer’s Coordinating Center cohort of 8,267 patients with Alzheimer’s disease and found a similar relationship between psychiatric history and age of onset among patients with depression or anxiety or both. This cohort also documented symptom severity, she noted. “So when we look at depression and anxiety we find similar reductions in the Alzheimer’s disease age of onset with each increasing degree of symptom severity,” she said.

“Does this mean that psychiatric disease is a risk factor for Alzheimr’s disease?” Ms. Eijansantos said. “We can’t answer that with this study because it was only designed to see if the psychiatric factors modulate the age of onset in those that have Alzheimer’s disease, but taken together we believe that these results fit the framework that there are pathophysiological and profound differences between earlier and later presentations of Alzheimer’s disease.”

She pointed to reports that early-onset Alzheimer’s disease is associated with more aggressive tau pathology and that depression is associated with tau. However, the evidence supporting a link between amyloid and psychiatric disease is less certain, she said.
 

Preliminary and speculative findings

Senior study author Zachary Miller, MD, an assistant professor in the UCSF Memory and Aging Center, explained the significance of the study findings of potential links between depression and autoimmunity, and anxiety and seizure. “There may be distinct underlying pathophysiological mechanisms in patients with Alzheimer’s disease who have symptoms of depression versus anxiety,” he said, acknowledging the findings “are quite preliminary and our interpretations quite speculative.”

The findings raise the question that the symptomatic presentation of greater amounts of depression in early-onset Alzheimer’s disease may be moderated by an underlying neuroinflammatory insult, he said. “If so, depression symptomatology could then be seen as a possible clinical marker of this inflammatory response and possibly be used in testing clinical endpoints for future intervention trials,” Dr. Miller said. “Similarly, if neuronal hyperexcitability in Alzheimer’s disease manifests itself as either seizure and/or anxiety, this would have significant impact for therapeutic monitoring and treatment.”

He said a multicenter study of Alzheimer’s disease cohorts would validate the findings. “At the same time, we are also interested in looking deeper into these findings, investigating the potential cognitive and neuroanatomical correlates associated with these conditions,” Dr. Miller said.

Clinical phenotyping may provide more insight into the relationship between psychosis and age of Alzheimer’s disease onset, said Vijay K. Ramanan, MD, PhD, an assistant professor of neurology at Mayo Clinic in Rochester, Minn.

People with clinically diagnosed depression and anxiety may be prone to developing Alzheimer’s disease at a younger age than other people, and those with a history of posttraumatic stress disorder may be prone to Alzheimer’s disease onset even earlier in life, according to findings from a review of 1,500 patients with Alzheimer’s disease from a single-center population.

“Could psychosis symptoms be the proverbial canary in a coal mine?” Emily Eijansantos, a medical student at the University of California, San Francisco, said in reporting results of the chart review at the 2021 annual meeting of the American Academy of Neurology. “Previously in this cohort it was found that neurodevelopmental factors as well as chronic insults such as autoimmunity and seizure were also associated with an early age of onset in Alzheimer’s disease.”

The link between depression and autoimmunity, and anxiety and seizure “beg more questions about underlying pathophysiology,” she said. The study included 750 patients with early-onset Alzheimer’s disease and a similar number of late-onset patients from the UCSF Memory and Aging Center.
 

An inverse correlation between psychiatric disorders and age of Alzheimer’s onset

In the total study population, 43.5% (n = 652) had a previous diagnosis of depression and 32.3% (n = 485) had been diagnosed with anxiety. That, Ms. Eijansantos said, falls into similar ranges that other studies have reported.

“When we look at individual psychiatric disorders, we find that those with depression, anxiety, or PTSD are younger on average,” she said. “Patients with depression and anxiety are more [likely] female and have less vascular risk factors, and we observed an association between depression and autoimmunity, anxiety, and seizures.”

Specifically, patients with a history of depression were 2.2 years younger, on average, at the age of onset than patients without such history (P = .01); those with anxiety were 3 years younger on average (P = .01); and those with PTSD were 6.8 years younger on average, although only 1% (n = 15) of study subjects had PTSD, making for a small sample to study. These age-of-onset disparities didn’t appear among patients with previously diagnosed bipolar disorder (BPD) or schizophrenia.

Ms. Eijansantos noted that there were no differences in education attained or apolipoprotein-E gene status between the patients with and without a history of psychosis, and, within the subgroups of individual psychiatric disorders, there were no differences between patients with past and current or formal and informal diagnoses.

“When we split the cohort into quintiles based on age of Alzheimer’s disease onset, we find an inverse correlation between the amount of depression, anxiety, and PTSD endorsed and their ages of onset,” Ms. Eijansantos said. For example, the youngest quintile had a greater than 50% rate of depression while the oldest quintile had a depression rate around 36%. A similar spread was found with anxiety: a rate around 46% in the youngest quantile versus around 25% in the oldest, whereas rates of PTSD, BPD, and schizophrenia were similar across the five age-of-onset groups.

Patients with a history of multiple psychiatric disorders had an even younger age of onset. “We see that those with two psychiatric disorder are younger than those with one, and those with three psychiatric disorders are younger still,” Ms. Eijansantos said. “And we find that the Alzheimer’s disease age-at-onset reduction doubles with each additional psychiatric disorder.” Multiple disorders also adversely impacted survival, she said.

Because they found no difference between patients with past versus active symptoms and informal versus formal diagnosis, Ms. Eijansantos explained that they further studied the National Alzheimer’s Coordinating Center cohort of 8,267 patients with Alzheimer’s disease and found a similar relationship between psychiatric history and age of onset among patients with depression or anxiety or both. This cohort also documented symptom severity, she noted. “So when we look at depression and anxiety we find similar reductions in the Alzheimer’s disease age of onset with each increasing degree of symptom severity,” she said.

“Does this mean that psychiatric disease is a risk factor for Alzheimr’s disease?” Ms. Eijansantos said. “We can’t answer that with this study because it was only designed to see if the psychiatric factors modulate the age of onset in those that have Alzheimer’s disease, but taken together we believe that these results fit the framework that there are pathophysiological and profound differences between earlier and later presentations of Alzheimer’s disease.”

She pointed to reports that early-onset Alzheimer’s disease is associated with more aggressive tau pathology and that depression is associated with tau. However, the evidence supporting a link between amyloid and psychiatric disease is less certain, she said.
 

Preliminary and speculative findings

Senior study author Zachary Miller, MD, an assistant professor in the UCSF Memory and Aging Center, explained the significance of the study findings of potential links between depression and autoimmunity, and anxiety and seizure. “There may be distinct underlying pathophysiological mechanisms in patients with Alzheimer’s disease who have symptoms of depression versus anxiety,” he said, acknowledging the findings “are quite preliminary and our interpretations quite speculative.”

The findings raise the question that the symptomatic presentation of greater amounts of depression in early-onset Alzheimer’s disease may be moderated by an underlying neuroinflammatory insult, he said. “If so, depression symptomatology could then be seen as a possible clinical marker of this inflammatory response and possibly be used in testing clinical endpoints for future intervention trials,” Dr. Miller said. “Similarly, if neuronal hyperexcitability in Alzheimer’s disease manifests itself as either seizure and/or anxiety, this would have significant impact for therapeutic monitoring and treatment.”

He said a multicenter study of Alzheimer’s disease cohorts would validate the findings. “At the same time, we are also interested in looking deeper into these findings, investigating the potential cognitive and neuroanatomical correlates associated with these conditions,” Dr. Miller said.

Clinical phenotyping may provide more insight into the relationship between psychosis and age of Alzheimer’s disease onset, said Vijay K. Ramanan, MD, PhD, an assistant professor of neurology at Mayo Clinic in Rochester, Minn.

People with clinically diagnosed depression and anxiety may be prone to developing Alzheimer’s disease at a younger age than other people, and those with a history of posttraumatic stress disorder may be prone to Alzheimer’s disease onset even earlier in life, according to findings from a review of 1,500 patients with Alzheimer’s disease from a single-center population.

“Could psychosis symptoms be the proverbial canary in a coal mine?” Emily Eijansantos, a medical student at the University of California, San Francisco, said in reporting results of the chart review at the 2021 annual meeting of the American Academy of Neurology. “Previously in this cohort it was found that neurodevelopmental factors as well as chronic insults such as autoimmunity and seizure were also associated with an early age of onset in Alzheimer’s disease.”

The link between depression and autoimmunity, and anxiety and seizure “beg more questions about underlying pathophysiology,” she said. The study included 750 patients with early-onset Alzheimer’s disease and a similar number of late-onset patients from the UCSF Memory and Aging Center.
 

An inverse correlation between psychiatric disorders and age of Alzheimer’s onset

In the total study population, 43.5% (n = 652) had a previous diagnosis of depression and 32.3% (n = 485) had been diagnosed with anxiety. That, Ms. Eijansantos said, falls into similar ranges that other studies have reported.

“When we look at individual psychiatric disorders, we find that those with depression, anxiety, or PTSD are younger on average,” she said. “Patients with depression and anxiety are more [likely] female and have less vascular risk factors, and we observed an association between depression and autoimmunity, anxiety, and seizures.”

Specifically, patients with a history of depression were 2.2 years younger, on average, at the age of onset than patients without such history (P = .01); those with anxiety were 3 years younger on average (P = .01); and those with PTSD were 6.8 years younger on average, although only 1% (n = 15) of study subjects had PTSD, making for a small sample to study. These age-of-onset disparities didn’t appear among patients with previously diagnosed bipolar disorder (BPD) or schizophrenia.

Ms. Eijansantos noted that there were no differences in education attained or apolipoprotein-E gene status between the patients with and without a history of psychosis, and, within the subgroups of individual psychiatric disorders, there were no differences between patients with past and current or formal and informal diagnoses.

“When we split the cohort into quintiles based on age of Alzheimer’s disease onset, we find an inverse correlation between the amount of depression, anxiety, and PTSD endorsed and their ages of onset,” Ms. Eijansantos said. For example, the youngest quintile had a greater than 50% rate of depression while the oldest quintile had a depression rate around 36%. A similar spread was found with anxiety: a rate around 46% in the youngest quantile versus around 25% in the oldest, whereas rates of PTSD, BPD, and schizophrenia were similar across the five age-of-onset groups.

Patients with a history of multiple psychiatric disorders had an even younger age of onset. “We see that those with two psychiatric disorder are younger than those with one, and those with three psychiatric disorders are younger still,” Ms. Eijansantos said. “And we find that the Alzheimer’s disease age-at-onset reduction doubles with each additional psychiatric disorder.” Multiple disorders also adversely impacted survival, she said.

Because they found no difference between patients with past versus active symptoms and informal versus formal diagnosis, Ms. Eijansantos explained that they further studied the National Alzheimer’s Coordinating Center cohort of 8,267 patients with Alzheimer’s disease and found a similar relationship between psychiatric history and age of onset among patients with depression or anxiety or both. This cohort also documented symptom severity, she noted. “So when we look at depression and anxiety we find similar reductions in the Alzheimer’s disease age of onset with each increasing degree of symptom severity,” she said.

“Does this mean that psychiatric disease is a risk factor for Alzheimr’s disease?” Ms. Eijansantos said. “We can’t answer that with this study because it was only designed to see if the psychiatric factors modulate the age of onset in those that have Alzheimer’s disease, but taken together we believe that these results fit the framework that there are pathophysiological and profound differences between earlier and later presentations of Alzheimer’s disease.”

She pointed to reports that early-onset Alzheimer’s disease is associated with more aggressive tau pathology and that depression is associated with tau. However, the evidence supporting a link between amyloid and psychiatric disease is less certain, she said.
 

Preliminary and speculative findings

Senior study author Zachary Miller, MD, an assistant professor in the UCSF Memory and Aging Center, explained the significance of the study findings of potential links between depression and autoimmunity, and anxiety and seizure. “There may be distinct underlying pathophysiological mechanisms in patients with Alzheimer’s disease who have symptoms of depression versus anxiety,” he said, acknowledging the findings “are quite preliminary and our interpretations quite speculative.”

The findings raise the question that the symptomatic presentation of greater amounts of depression in early-onset Alzheimer’s disease may be moderated by an underlying neuroinflammatory insult, he said. “If so, depression symptomatology could then be seen as a possible clinical marker of this inflammatory response and possibly be used in testing clinical endpoints for future intervention trials,” Dr. Miller said. “Similarly, if neuronal hyperexcitability in Alzheimer’s disease manifests itself as either seizure and/or anxiety, this would have significant impact for therapeutic monitoring and treatment.”

He said a multicenter study of Alzheimer’s disease cohorts would validate the findings. “At the same time, we are also interested in looking deeper into these findings, investigating the potential cognitive and neuroanatomical correlates associated with these conditions,” Dr. Miller said.

Clinical phenotyping may provide more insight into the relationship between psychosis and age of Alzheimer’s disease onset, said Vijay K. Ramanan, MD, PhD, an assistant professor of neurology at Mayo Clinic in Rochester, Minn.

Deep brain stimulation (DBS) significantly improves motor function in patients with Parkinson’s disease over the long term, regardless of the therapeutic target, new research shows. In the longest follow-up study comparing the subthalamic nucleus (STN) or the globus pallidus (GPi) as treatment targets for Parkinson’s disease, investigators found DBS was effective at 10 years regardless of which of these two brain regions were treated.

“Both STN and GPi DBS maintained motor benefit out to 10 years, with improvements seen in tremor and rigidity, greater than bradykinesia,” said study author Jill L. Ostrem, MD, medical director and division chief at the University of California, San Francisco Movement Disorders and Neuromodulation Center.

“Less medication was required, and patients had fewer motor fluctuations and less dyskinesia,” she added. But nonmotor symptoms and other symptoms that are less responsive to DBS progress led to worsening disability over time.

The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Advanced patients  

Many studies have examined the GPi and STN as targets for deep brain stimulation in Parkinson’s disease. Some research has compared outcomes between the two targets, but no prospective, randomized trials have evaluated outcomes beyond 3 years of treatment.

For the study, investigators examined data from Study 468, a multicenter, randomized, controlled trial conducted by the U.S. Veterans Affairs (VA) Cooperative Study Program and the National Institute of Neurological Disorders and Stroke (NINDS). In this study, a subset of patients who had been randomly assigned to deep brain stimulation of the GPi or STN were followed for up to 10 years.

Participants were examined at 2 years, 7 years, and 10 years. Eighty-five participants assigned to GPi and 70 assigned to STN completed the visit at 2 years. At 7 years, 68 GPi patients and 49 STN patients completed the visit. Forty-nine patients assigned to GPi and 28 assigned to STN completed the visit at 10 years.

The study’s primary outcome was change in the Unified Parkinson Disease Rating Scale (UPDRS) motor subscale score while off medication and on stimulation between targets. Secondary outcomes included tremor, rigidity, and bradykinesia.

The two groups of patients had comparable baseline characteristics. Mean age was approximately 59 years in both groups. The proportion of male patients was 87% in the GPi group and 83% in the STN group. White patients predominated in the GPi (98%) and STN (94%) groups.

Average disease duration was approximately 11 years, and more than 10% of patients in each group were older than 70 years, indicating a “somewhat more advanced patient cohort,” said Dr. Ostrem.

Although the study’s dropout rate was high, the researchers found no difference in baseline characteristics between patients who did and did not complete the study.
 

Consistent motor improvement

Motor function improved at all timepoints for patients in both study arms. Baseline UPDRS motor subscale score was 43.2 for patients assigned to GPi stimulation. This score changed to 25.8 at 2 years (P < .001), 35.4 at 7 years (P < .001), and 34.0 at 10 years (P = .10).

Baseline UPDRS motor subscale score also was 43.2 for patients assigned to STN stimulation. This score changed to 27.7 at 2 years (P < .001), 34.4 at 7 years (P < .001), and 28.3 at 10 years (P < .001). Improvements were similar between groups but tended to be greater in the STN group.

Among the study’s secondary outcomes, tremor subscales showed the greatest improvement over time, followed by rigidity subscores. Compared with GPi DBS, STN DBS was associated with greater improvement in bradykinesia subscores at 7 and 10 years (P = .03).

In addition, UPDRS I, II, and IV scores, as recorded in motor diaries, showed significant long-term improvement in both study groups. Part I (which reflects mentation and mood) and part II (which reflects activities of daily living) tended to worsen at 7 and 10 years. There were no differences between groups.

Total score on the Parkinson’s Disease Questionnaire-39 (PDQ-39), which measures function in daily living, no longer showed improvement at 7 or 10 years for either target. Rather, it showed worsening, compared with baseline.

“Cognitive impairment and gait and balance issues result in more issues with quality of life and independence,” said Dr. Ostrem.

Stimulation of both targets reduced medication use significantly. There was no difference between targets for this outcome.

The rate of device-related complications in this cohort was comparatively low, said Dr. Ostrem. In the overall study complication, the rate of DBS malfunction was 7.7%, and the rate of DBS infection was 5.8%.

The finding that both targets had similar long-term sustainability of motor benefit provides reassurance that either target is a reasonable choice, said Dr. Ostrem. “I would suggest target choice be determined by a multidisciplinary team, where individual patient signs and symptoms and goals can be considered.”

Other large DBS trials with shorter follow-up durations have suggested differences between the targets. These data can guide the choice of target, said Dr. Ostrem.

“The field of DBS research has never been more exciting,” she added. Newer systems that include improved hardware and software and can record neurophysiologic data from the implanted brain leads could provide improved outcomes of DBS treatment. 

“With modern DBS methods and approaches, we are learning more about Parkinson’s disease and other brain diseases, which I believe will help us to find more treatments and other interventions to slow the progression or minimize symptoms,” Dr. Ostrem concluded.
 

Selection bias?

Commenting on the study, Alfonso Fasano, MD, PhD, chair in neuromodulation and multidisciplinary care at University of Toronto, noted that “these are the first long-term findings resulting from a randomized trial, overall supporting the early notion that STN DBS is superior to GPi DBS in terms of bradykinesia improvement, especially in the long-run.”

The findings reflect the clinical practice of considering STN deep brain stimulation for young patients who face a longer disease duration. Younger patients might tolerate the procedure better than older patients. They also may achieve medication reduction, better motor control, and the possibility of increasing medication when side effects make increased stimulation undesirable.

“It’s interesting to note that even GPi DBS maintained an overall good outcome over time,” said Dr. Fasano. This finding contrasts with that of previous studies, but the latter were limited by selection bias, he added. “Older and frail patients were more likely to be treated with GPi DBS.”

Two factors limit the study’s findings, said Dr. Fasano. During the long study duration, many patients dropped out or were lost to follow-up. “Thus, it is conceivable that the study only enrolled the best responders in each group,” said Dr. Fasano.

In addition, the results of the trial that the current investigators analyzed are not necessarily generalizable, as those who conducted it soon recognized. The study by the VA and NINDS did not detect differences between targets, mainly because of a surprisingly low effect of STN deep brain stimulation. The researchers determined that this finding was related to the study’s inclusion criteria.

“The lack of improvement [on the PDQ-39] clearly indicates that simply treating the motor problems of Parkinson’s disease patients is not enough,” said Dr. Fasano. It also emphasizes that DBS is a symptomatic therapy with little or no effect on the disease’s natural history.

“It will be also important to see how the new data reported by Dr. Ostrem compare to the long-term outcome of the other major STN versus GPi trial from Europe,” said Dr. Fasano, referring to the NSTAPS trial.

He added that it will also be interesting to follow these cohorts for at least 5 more years in order to identify possible differences in terms of disease milestones such as dementia and survival. Previous studies have shown a reduction in survival with targets other than STN, but this finding likely reflects selection bias, he concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke and the U.S. Department of Veterans Affairs. Dr. Ostrem previously has accepted consulting funds from Medtronic and Abbott. She receives grant support from Medtronic and Boston Scientific for fellowship training and clinical trial support. These companies were not involved in the study. Dr. Fasano received honoraria and research support and honoraria from Abbott, Boston Scientific, Brainlab, Ceregate, Inbrain, and Medtronic.

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

Deep brain stimulation (DBS) significantly improves motor function in patients with Parkinson’s disease over the long term, regardless of the therapeutic target, new research shows. In the longest follow-up study comparing the subthalamic nucleus (STN) or the globus pallidus (GPi) as treatment targets for Parkinson’s disease, investigators found DBS was effective at 10 years regardless of which of these two brain regions were treated.

“Both STN and GPi DBS maintained motor benefit out to 10 years, with improvements seen in tremor and rigidity, greater than bradykinesia,” said study author Jill L. Ostrem, MD, medical director and division chief at the University of California, San Francisco Movement Disorders and Neuromodulation Center.

“Less medication was required, and patients had fewer motor fluctuations and less dyskinesia,” she added. But nonmotor symptoms and other symptoms that are less responsive to DBS progress led to worsening disability over time.

The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Advanced patients  

Many studies have examined the GPi and STN as targets for deep brain stimulation in Parkinson’s disease. Some research has compared outcomes between the two targets, but no prospective, randomized trials have evaluated outcomes beyond 3 years of treatment.

For the study, investigators examined data from Study 468, a multicenter, randomized, controlled trial conducted by the U.S. Veterans Affairs (VA) Cooperative Study Program and the National Institute of Neurological Disorders and Stroke (NINDS). In this study, a subset of patients who had been randomly assigned to deep brain stimulation of the GPi or STN were followed for up to 10 years.

Participants were examined at 2 years, 7 years, and 10 years. Eighty-five participants assigned to GPi and 70 assigned to STN completed the visit at 2 years. At 7 years, 68 GPi patients and 49 STN patients completed the visit. Forty-nine patients assigned to GPi and 28 assigned to STN completed the visit at 10 years.

The study’s primary outcome was change in the Unified Parkinson Disease Rating Scale (UPDRS) motor subscale score while off medication and on stimulation between targets. Secondary outcomes included tremor, rigidity, and bradykinesia.

The two groups of patients had comparable baseline characteristics. Mean age was approximately 59 years in both groups. The proportion of male patients was 87% in the GPi group and 83% in the STN group. White patients predominated in the GPi (98%) and STN (94%) groups.

Average disease duration was approximately 11 years, and more than 10% of patients in each group were older than 70 years, indicating a “somewhat more advanced patient cohort,” said Dr. Ostrem.

Although the study’s dropout rate was high, the researchers found no difference in baseline characteristics between patients who did and did not complete the study.
 

Consistent motor improvement

Motor function improved at all timepoints for patients in both study arms. Baseline UPDRS motor subscale score was 43.2 for patients assigned to GPi stimulation. This score changed to 25.8 at 2 years (P < .001), 35.4 at 7 years (P < .001), and 34.0 at 10 years (P = .10).

Baseline UPDRS motor subscale score also was 43.2 for patients assigned to STN stimulation. This score changed to 27.7 at 2 years (P < .001), 34.4 at 7 years (P < .001), and 28.3 at 10 years (P < .001). Improvements were similar between groups but tended to be greater in the STN group.

Among the study’s secondary outcomes, tremor subscales showed the greatest improvement over time, followed by rigidity subscores. Compared with GPi DBS, STN DBS was associated with greater improvement in bradykinesia subscores at 7 and 10 years (P = .03).

In addition, UPDRS I, II, and IV scores, as recorded in motor diaries, showed significant long-term improvement in both study groups. Part I (which reflects mentation and mood) and part II (which reflects activities of daily living) tended to worsen at 7 and 10 years. There were no differences between groups.

Total score on the Parkinson’s Disease Questionnaire-39 (PDQ-39), which measures function in daily living, no longer showed improvement at 7 or 10 years for either target. Rather, it showed worsening, compared with baseline.

“Cognitive impairment and gait and balance issues result in more issues with quality of life and independence,” said Dr. Ostrem.

Stimulation of both targets reduced medication use significantly. There was no difference between targets for this outcome.

The rate of device-related complications in this cohort was comparatively low, said Dr. Ostrem. In the overall study complication, the rate of DBS malfunction was 7.7%, and the rate of DBS infection was 5.8%.

The finding that both targets had similar long-term sustainability of motor benefit provides reassurance that either target is a reasonable choice, said Dr. Ostrem. “I would suggest target choice be determined by a multidisciplinary team, where individual patient signs and symptoms and goals can be considered.”

Other large DBS trials with shorter follow-up durations have suggested differences between the targets. These data can guide the choice of target, said Dr. Ostrem.

“The field of DBS research has never been more exciting,” she added. Newer systems that include improved hardware and software and can record neurophysiologic data from the implanted brain leads could provide improved outcomes of DBS treatment. 

“With modern DBS methods and approaches, we are learning more about Parkinson’s disease and other brain diseases, which I believe will help us to find more treatments and other interventions to slow the progression or minimize symptoms,” Dr. Ostrem concluded.
 

Selection bias?

Commenting on the study, Alfonso Fasano, MD, PhD, chair in neuromodulation and multidisciplinary care at University of Toronto, noted that “these are the first long-term findings resulting from a randomized trial, overall supporting the early notion that STN DBS is superior to GPi DBS in terms of bradykinesia improvement, especially in the long-run.”

The findings reflect the clinical practice of considering STN deep brain stimulation for young patients who face a longer disease duration. Younger patients might tolerate the procedure better than older patients. They also may achieve medication reduction, better motor control, and the possibility of increasing medication when side effects make increased stimulation undesirable.

“It’s interesting to note that even GPi DBS maintained an overall good outcome over time,” said Dr. Fasano. This finding contrasts with that of previous studies, but the latter were limited by selection bias, he added. “Older and frail patients were more likely to be treated with GPi DBS.”

Two factors limit the study’s findings, said Dr. Fasano. During the long study duration, many patients dropped out or were lost to follow-up. “Thus, it is conceivable that the study only enrolled the best responders in each group,” said Dr. Fasano.

In addition, the results of the trial that the current investigators analyzed are not necessarily generalizable, as those who conducted it soon recognized. The study by the VA and NINDS did not detect differences between targets, mainly because of a surprisingly low effect of STN deep brain stimulation. The researchers determined that this finding was related to the study’s inclusion criteria.

“The lack of improvement [on the PDQ-39] clearly indicates that simply treating the motor problems of Parkinson’s disease patients is not enough,” said Dr. Fasano. It also emphasizes that DBS is a symptomatic therapy with little or no effect on the disease’s natural history.

“It will be also important to see how the new data reported by Dr. Ostrem compare to the long-term outcome of the other major STN versus GPi trial from Europe,” said Dr. Fasano, referring to the NSTAPS trial.

He added that it will also be interesting to follow these cohorts for at least 5 more years in order to identify possible differences in terms of disease milestones such as dementia and survival. Previous studies have shown a reduction in survival with targets other than STN, but this finding likely reflects selection bias, he concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke and the U.S. Department of Veterans Affairs. Dr. Ostrem previously has accepted consulting funds from Medtronic and Abbott. She receives grant support from Medtronic and Boston Scientific for fellowship training and clinical trial support. These companies were not involved in the study. Dr. Fasano received honoraria and research support and honoraria from Abbott, Boston Scientific, Brainlab, Ceregate, Inbrain, and Medtronic.

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

Deep brain stimulation (DBS) significantly improves motor function in patients with Parkinson’s disease over the long term, regardless of the therapeutic target, new research shows. In the longest follow-up study comparing the subthalamic nucleus (STN) or the globus pallidus (GPi) as treatment targets for Parkinson’s disease, investigators found DBS was effective at 10 years regardless of which of these two brain regions were treated.

“Both STN and GPi DBS maintained motor benefit out to 10 years, with improvements seen in tremor and rigidity, greater than bradykinesia,” said study author Jill L. Ostrem, MD, medical director and division chief at the University of California, San Francisco Movement Disorders and Neuromodulation Center.

“Less medication was required, and patients had fewer motor fluctuations and less dyskinesia,” she added. But nonmotor symptoms and other symptoms that are less responsive to DBS progress led to worsening disability over time.

The findings were presented at the American Academy of Neurology’s 2021 annual meeting.
 

Advanced patients  

Many studies have examined the GPi and STN as targets for deep brain stimulation in Parkinson’s disease. Some research has compared outcomes between the two targets, but no prospective, randomized trials have evaluated outcomes beyond 3 years of treatment.

For the study, investigators examined data from Study 468, a multicenter, randomized, controlled trial conducted by the U.S. Veterans Affairs (VA) Cooperative Study Program and the National Institute of Neurological Disorders and Stroke (NINDS). In this study, a subset of patients who had been randomly assigned to deep brain stimulation of the GPi or STN were followed for up to 10 years.

Participants were examined at 2 years, 7 years, and 10 years. Eighty-five participants assigned to GPi and 70 assigned to STN completed the visit at 2 years. At 7 years, 68 GPi patients and 49 STN patients completed the visit. Forty-nine patients assigned to GPi and 28 assigned to STN completed the visit at 10 years.

The study’s primary outcome was change in the Unified Parkinson Disease Rating Scale (UPDRS) motor subscale score while off medication and on stimulation between targets. Secondary outcomes included tremor, rigidity, and bradykinesia.

The two groups of patients had comparable baseline characteristics. Mean age was approximately 59 years in both groups. The proportion of male patients was 87% in the GPi group and 83% in the STN group. White patients predominated in the GPi (98%) and STN (94%) groups.

Average disease duration was approximately 11 years, and more than 10% of patients in each group were older than 70 years, indicating a “somewhat more advanced patient cohort,” said Dr. Ostrem.

Although the study’s dropout rate was high, the researchers found no difference in baseline characteristics between patients who did and did not complete the study.
 

Consistent motor improvement

Motor function improved at all timepoints for patients in both study arms. Baseline UPDRS motor subscale score was 43.2 for patients assigned to GPi stimulation. This score changed to 25.8 at 2 years (P < .001), 35.4 at 7 years (P < .001), and 34.0 at 10 years (P = .10).

Baseline UPDRS motor subscale score also was 43.2 for patients assigned to STN stimulation. This score changed to 27.7 at 2 years (P < .001), 34.4 at 7 years (P < .001), and 28.3 at 10 years (P < .001). Improvements were similar between groups but tended to be greater in the STN group.

Among the study’s secondary outcomes, tremor subscales showed the greatest improvement over time, followed by rigidity subscores. Compared with GPi DBS, STN DBS was associated with greater improvement in bradykinesia subscores at 7 and 10 years (P = .03).

In addition, UPDRS I, II, and IV scores, as recorded in motor diaries, showed significant long-term improvement in both study groups. Part I (which reflects mentation and mood) and part II (which reflects activities of daily living) tended to worsen at 7 and 10 years. There were no differences between groups.

Total score on the Parkinson’s Disease Questionnaire-39 (PDQ-39), which measures function in daily living, no longer showed improvement at 7 or 10 years for either target. Rather, it showed worsening, compared with baseline.

“Cognitive impairment and gait and balance issues result in more issues with quality of life and independence,” said Dr. Ostrem.

Stimulation of both targets reduced medication use significantly. There was no difference between targets for this outcome.

The rate of device-related complications in this cohort was comparatively low, said Dr. Ostrem. In the overall study complication, the rate of DBS malfunction was 7.7%, and the rate of DBS infection was 5.8%.

The finding that both targets had similar long-term sustainability of motor benefit provides reassurance that either target is a reasonable choice, said Dr. Ostrem. “I would suggest target choice be determined by a multidisciplinary team, where individual patient signs and symptoms and goals can be considered.”

Other large DBS trials with shorter follow-up durations have suggested differences between the targets. These data can guide the choice of target, said Dr. Ostrem.

“The field of DBS research has never been more exciting,” she added. Newer systems that include improved hardware and software and can record neurophysiologic data from the implanted brain leads could provide improved outcomes of DBS treatment. 

“With modern DBS methods and approaches, we are learning more about Parkinson’s disease and other brain diseases, which I believe will help us to find more treatments and other interventions to slow the progression or minimize symptoms,” Dr. Ostrem concluded.
 

Selection bias?

Commenting on the study, Alfonso Fasano, MD, PhD, chair in neuromodulation and multidisciplinary care at University of Toronto, noted that “these are the first long-term findings resulting from a randomized trial, overall supporting the early notion that STN DBS is superior to GPi DBS in terms of bradykinesia improvement, especially in the long-run.”

The findings reflect the clinical practice of considering STN deep brain stimulation for young patients who face a longer disease duration. Younger patients might tolerate the procedure better than older patients. They also may achieve medication reduction, better motor control, and the possibility of increasing medication when side effects make increased stimulation undesirable.

“It’s interesting to note that even GPi DBS maintained an overall good outcome over time,” said Dr. Fasano. This finding contrasts with that of previous studies, but the latter were limited by selection bias, he added. “Older and frail patients were more likely to be treated with GPi DBS.”

Two factors limit the study’s findings, said Dr. Fasano. During the long study duration, many patients dropped out or were lost to follow-up. “Thus, it is conceivable that the study only enrolled the best responders in each group,” said Dr. Fasano.

In addition, the results of the trial that the current investigators analyzed are not necessarily generalizable, as those who conducted it soon recognized. The study by the VA and NINDS did not detect differences between targets, mainly because of a surprisingly low effect of STN deep brain stimulation. The researchers determined that this finding was related to the study’s inclusion criteria.

“The lack of improvement [on the PDQ-39] clearly indicates that simply treating the motor problems of Parkinson’s disease patients is not enough,” said Dr. Fasano. It also emphasizes that DBS is a symptomatic therapy with little or no effect on the disease’s natural history.

“It will be also important to see how the new data reported by Dr. Ostrem compare to the long-term outcome of the other major STN versus GPi trial from Europe,” said Dr. Fasano, referring to the NSTAPS trial.

He added that it will also be interesting to follow these cohorts for at least 5 more years in order to identify possible differences in terms of disease milestones such as dementia and survival. Previous studies have shown a reduction in survival with targets other than STN, but this finding likely reflects selection bias, he concluded.

The study was funded by the National Institute of Neurological Disorders and Stroke and the U.S. Department of Veterans Affairs. Dr. Ostrem previously has accepted consulting funds from Medtronic and Abbott. She receives grant support from Medtronic and Boston Scientific for fellowship training and clinical trial support. These companies were not involved in the study. Dr. Fasano received honoraria and research support and honoraria from Abbott, Boston Scientific, Brainlab, Ceregate, Inbrain, and Medtronic.

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

COVID-19 is linked to novel seizures and subsequent adverse outcomes, including death, in patients without a previous history of epilepsy, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.

In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.

“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.

Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”

“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.

Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
 

Largest sample to date

“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.

Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.

However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.

For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.

For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).

The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
 

Significant adverse outcomes

Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).

In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).

In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).

Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).

Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.

Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”

He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”

Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.

The investigators have reported no relevant financial relationships.

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

COVID-19 is linked to novel seizures and subsequent adverse outcomes, including death, in patients without a previous history of epilepsy, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.

In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.

“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.

Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”

“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.

Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
 

Largest sample to date

“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.

Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.

However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.

For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.

For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).

The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
 

Significant adverse outcomes

Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).

In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).

In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).

Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).

Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.

Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”

He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”

Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.

The investigators have reported no relevant financial relationships.

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

COVID-19 is linked to novel seizures and subsequent adverse outcomes, including death, in patients without a previous history of epilepsy, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.

In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.

“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.

Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”

“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.

Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
 

Largest sample to date

“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.

Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.

However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.

For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.

For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).

The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
 

Significant adverse outcomes

Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).

In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).

In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).

Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).

Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.

Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”

He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”

Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.

The investigators have reported no relevant financial relationships.

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