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Erik Greb joined the staff of Neurology Reviews in January 2012. Since then, he has attended scientific conferences, conducted video interviews, and written about clinical research in multiple sclerosis, epilepsy, Parkinson's disease, Alzheimer's disease, stroke, and other neurologic disorders. In addition to news articles, Erik has written investigative stories about multiple sclerosis, headache, and epilepsy. He previously wrote about pharmaceutical manufacturing, drug formulation and delivery, quality assurance, and regulation for Pharmaceutical Technology.
Cortical lesions predict risk for secondary progressive MS
(MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.
In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.
“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.
The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Accumulation of disability
Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.
The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.
At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.
The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
Lesions and disease progression
At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.
At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.
The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).
In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).
The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.
In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
‘Important study’
“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.
Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.
“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.
While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.
Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”
One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.
The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.
In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.
“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.
The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Accumulation of disability
Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.
The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.
At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.
The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
Lesions and disease progression
At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.
At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.
The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).
In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).
The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.
In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
‘Important study’
“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.
Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.
“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.
While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.
Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”
One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.
The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
(MS), according to new research. Cortical lesions also may be an early marker of future disability accumulation.
In the study, patients who had developed secondary progressive MS after 20 years of follow-up had approximately 7 cortical lesions at baseline. This number was significantly higher than the baseline number of cortical lesions in patients with clinically isolated syndrome (CIS), relapsing-remitting MS, or primary progressive MS at 20 years.
“Our study represented a clear indication that the assessment, presence, and high number of cortical lesions at diagnosis is one of the tools at the disposal of the neurologist for the early identification of patients with more serious disease course,” said Gian Marco Schiavi, MD, a neurology resident at the University of Verona, Italy, during the presentation of his research.
The study was presented October 14 at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
Accumulation of disability
Previous research has indicated that cortical lesions play a role in the accumulation of disability in MS and the conversion to secondary progressive MS. Other observations suggest that the number of cortical lesions after 30 years of follow-up explains more than 40% of the difference in disability between patients with secondary progressive MS.
The current investigators sought to understand whether cortical lesions at diagnosis could predict a patient’s risk for development of secondary progressive MS and risk for disability accumulation. They included 220 patients with MS and approximately 20 years of follow-up in their study.
At the time of diagnosis, all participants underwent 1.5-T MRI with double inversion recovery. Participants also presented for periodic MRI and clinical evaluations.
The researchers used analysis of variance to compare the baseline number of cortical lesions between patients with CIS, relapsing-remitting MS, secondary progressive MS, and primary progressive MS at 20 years. They also performed a multivariable regression analysis to predict patients’ final scores on the Expanded Disability Status Scale (EDSS). Variables included participants’ demographic, clinical, and radiological characteristics.
Lesions and disease progression
At baseline (the time of diagnosis), 162 patients had relapsing-remitting MS, 45 had CIS, and 12 had primary progressive MS. In all, 106 patients had no cortical lesions, 47 had 3 or fewer cortical lesions, and 67 had more than 3 cortical lesions.
At 20 years, 12 patients still had CIS, 152 had relapsing-remitting MS, and 44 had developed secondary progressive MS.
The mean number of cortical lesions at diagnosis was 6.6 in patients with secondary progressive MS at 20 years, which was significantly higher than the mean 1.3 cortical lesions in the other patients (P < .001).
In addition, post-hoc analysis showed that the median number of cortical lesions was significantly higher in patients with secondary progressive MS (6), compared with those with CIS (0; P < .001), relapsing-remitting MS (0; P < .001), and primary progressive MS (4.5; P = .013). Patients with primary progressive MS had a higher number of cortical lesions than patients with CIS and those with relapsing-remitting MS (P = .001).
The investigators also examined disability at 20 years. At that timepoint, mean EDSS score was 1.5 in patients with no cortical lesions, 3.0 in patients with 1 to 3 cortical lesions at baseline, and 6.0 in patients with more than 3 cortical lesions.
In a regression analysis, the number of cortical lesions and EDSS at diagnosis were the best predictors of long-term disability (P < .001). These factors explained about 57% of the variance in EDSS score after 20 years.
‘Important study’
“This important study supports that the presence of cortical lesions at the time of diagnosis is associated with long-term disability and transition to a secondary progressive disease course,” said Elias S. Sotirchos, MD, assistant professor of neurology at Johns Hopkins University, Baltimore. The study size and long duration of follow-up are important strengths of the findings, he added.
Still, further research is needed to validate cortical lesions as a biomarker in clinical practice. Aside from technical validation issues relating to the identification of cortical lesions, whether cortical lesion burden can be used to guide therapeutic decision-making in MS is not clear, said Dr. Sotirchos.
“Notably, these patients were diagnosed and enrolled in this study 20 years ago, prior to the availability of newer disease-modifying therapies [DMTs] that are more effective at preventing inflammatory disease activity in MS,” he said, referring to the participants in the current study.
While recent observational studies have suggested that early initiation of higher-efficacy disease-modifying therapies (DMTs) may reduce long-term disability and risk for transition to secondary progressive MS, the optimal approach to treatment in patients with a new diagnosis remains unclear, said Dr. Sotirchos.
Furthermore, it is unknown whether use of higher-efficacy DMTs may affect the risk of future disability in patients with high cortical lesion burden at baseline, said Dr. Sotirchos. “Or is it too late, especially considering the modest effects of DMTs in progressive patients and that cortical lesion burden was higher in patients that are progressive?”
One additional question to be addressed is how baseline cortical lesion burden adds to other factors that neurologists use in clinical practice to stratify patients’ risk of future disability, such as spinal cord involvement, motor or sphincter symptoms at onset, poor recovery from attacks, and white matter lesion burden, said Dr. Sotirchos.
The source of funding for this study was not reported. Dr. Schiavi and Dr. Sotirchos have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ECTRIMS 2021
ADHD med may reduce apathy in Alzheimer’s disease
Methylphenidate is safe and effective for treating apathy in patients with Alzheimer’s disease (AD), new research suggests.
Results from a phase 3 randomized trial showed that, after 6 months of treatment, mean score on the Neuropsychiatric Inventory (NPI) apathy subscale decreased by 4.5 points for patients who received methylphenidate vs. a decrease of 3.1 points for those who received placebo.
In addition, the safety profile showed no significant between-group differences.
“Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers,” said the investigators, led by Jacobo E. Mintzer, MD, MBA, professor of health studies at the Medical University of South Carolina in Charleston.
The findings were published online Sept. 27 in JAMA Neurology.
Common problem
Apathy, which is common among patients with AD, is associated with increased risk for mortality, financial burden, and caregiver burden. No treatment has proved effective for apathy in this population.
Two trials of methylphenidate, a catecholaminergic agent, have provided preliminary evidence of efficacy. Findings from the Apathy in Dementia Methylphenidate trial (ADMET) suggested the drug was associated with improved cognition and few adverse events. However, both trials had small patient populations and short durations.
The current investigators conducted ADMET 2, a 6-month, phase 3 trial, to investigate methylphenidate further. They recruited 200 patients (mean age, 76 years; 66% men; 90% White) at nine clinical centers that specialized in dementia care in the United States and one in Canada.
Eligible patients had a diagnosis of possible or probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 28. They also had clinically significant apathy for at least 4 weeks and an available caregiver who spent more than 10 hours a week with the patient.
The researchers randomly assigned patients to receive methylphenidate (n = 99) or placebo (n = 101). For 3 days, participants in the active group received 10 mg/day of methylphenidate. After that point, they received 20 mg/day of methylphenidate for the rest of the study.
Patients in both treatment groups were given the same number of identical-appearing capsules each day.
In-person follow-up visits took place monthly for 6 months. Participants also were contacted by telephone at days 15, 45, and 75 after treatment assignment.
Participants underwent cognitive testing at baseline and at 2, 4, and 6 months. The battery of tests included the MMSE, Hopkins Verbal Learning Test, and Wechsler Adult Intelligence Scale – Revised Digit Span.
The trial’s two primary outcomes were mean change in NPI apathy score from baseline to 6 months and the odds of an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) between baseline and 6 months.
Significant change on either outcome was to be considered a signal of effective treatment.
Treatment-specific benefit
Ten patients in the methylphenidate group and seven in the placebo group withdrew during the study.
Mean baseline score on the NPI apathy subscale was 8.0 vs. 7.6, respectively.
In an adjusted, longitudinal model, mean between-group difference in change in NPI apathy score at 6 months was –1.25 (P = .002). The mean NPI apathy score decreased by 4.5 points in the methylphenidate group vs. 3.1 points in the placebo group.
The largest change in apathy score occurred during the first 2 months of treatment. At 6 months, 27% of the methylphenidate group vs. 14% of the placebo group had an NPI apathy score of 0.
In addition, 43.8% of the methylphenidate group had improvement on the ADCS-CGIC compared with 35.2% of the placebo group. The odds ratio (OR) for improvement on ADCS-CGIC for methylphenidate vs. placebo was 1.90 (P = .07).
There was also a strong association between score improvement on the NPI apathy subscale and improvement on the ADCS-CGIC subscale (OR, 2.95; P = .002).
“It is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition,” the researchers wrote.
In all, 17 serious adverse events occurred in the methylphenidate group and 10 occurred in the placebo group. However, all events were found to be hospitalizations for events not related to treatment.
‘Enduring effect’
Commenting on the findings, Jeffrey L. Cummings, MD, ScD, professor of brain sciences at the University of Nevada, Las Vegas, noted that the reduction in NPI apathy subscale score of more than 50% was clinically meaningful.
A more robust outcome on the ADCS-CGIC would have been desirable, he added, although that instrument is not designed specifically for apathy.
Methylphenidate’s effect on apathy observed at 2 months and remaining stable throughout the study makes it appear to be “an enduring effect, and not something that the patient accommodates to,” said Dr. Cummings, who was not involved with the research. Such a change may manifest itself in a patient’s greater willingness to help voluntarily with housework or to suggest going for a walk, he noted.
“These are not dramatic changes in cognition, of course, but they are changes in initiative and that is very important,” Dr. Cummings said. Decreased apathy also may improve quality of life for the patient’s caregiver, he added.
Overall, the findings raise the question of whether the Food and Drug Administration should recognize apathy as an indication for which drugs can be approved, said Dr. Cummings.
“For me, that would be the next major step in this line of investigation,” he concluded.
The study was funded by the National Institute on Aging. Dr. Mintzer has served as an adviser to Praxis Bioresearch and Cerevel Therapeutics on matters unrelated to this study. Dr. Cummings is the author of the Neuropsychiatric Inventory but does not receive payments for it from academic trials such as ADMET 2.
A version of this article first appeared on Medscape.com.
Methylphenidate is safe and effective for treating apathy in patients with Alzheimer’s disease (AD), new research suggests.
Results from a phase 3 randomized trial showed that, after 6 months of treatment, mean score on the Neuropsychiatric Inventory (NPI) apathy subscale decreased by 4.5 points for patients who received methylphenidate vs. a decrease of 3.1 points for those who received placebo.
In addition, the safety profile showed no significant between-group differences.
“Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers,” said the investigators, led by Jacobo E. Mintzer, MD, MBA, professor of health studies at the Medical University of South Carolina in Charleston.
The findings were published online Sept. 27 in JAMA Neurology.
Common problem
Apathy, which is common among patients with AD, is associated with increased risk for mortality, financial burden, and caregiver burden. No treatment has proved effective for apathy in this population.
Two trials of methylphenidate, a catecholaminergic agent, have provided preliminary evidence of efficacy. Findings from the Apathy in Dementia Methylphenidate trial (ADMET) suggested the drug was associated with improved cognition and few adverse events. However, both trials had small patient populations and short durations.
The current investigators conducted ADMET 2, a 6-month, phase 3 trial, to investigate methylphenidate further. They recruited 200 patients (mean age, 76 years; 66% men; 90% White) at nine clinical centers that specialized in dementia care in the United States and one in Canada.
Eligible patients had a diagnosis of possible or probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 28. They also had clinically significant apathy for at least 4 weeks and an available caregiver who spent more than 10 hours a week with the patient.
The researchers randomly assigned patients to receive methylphenidate (n = 99) or placebo (n = 101). For 3 days, participants in the active group received 10 mg/day of methylphenidate. After that point, they received 20 mg/day of methylphenidate for the rest of the study.
Patients in both treatment groups were given the same number of identical-appearing capsules each day.
In-person follow-up visits took place monthly for 6 months. Participants also were contacted by telephone at days 15, 45, and 75 after treatment assignment.
Participants underwent cognitive testing at baseline and at 2, 4, and 6 months. The battery of tests included the MMSE, Hopkins Verbal Learning Test, and Wechsler Adult Intelligence Scale – Revised Digit Span.
The trial’s two primary outcomes were mean change in NPI apathy score from baseline to 6 months and the odds of an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) between baseline and 6 months.
Significant change on either outcome was to be considered a signal of effective treatment.
Treatment-specific benefit
Ten patients in the methylphenidate group and seven in the placebo group withdrew during the study.
Mean baseline score on the NPI apathy subscale was 8.0 vs. 7.6, respectively.
In an adjusted, longitudinal model, mean between-group difference in change in NPI apathy score at 6 months was –1.25 (P = .002). The mean NPI apathy score decreased by 4.5 points in the methylphenidate group vs. 3.1 points in the placebo group.
The largest change in apathy score occurred during the first 2 months of treatment. At 6 months, 27% of the methylphenidate group vs. 14% of the placebo group had an NPI apathy score of 0.
In addition, 43.8% of the methylphenidate group had improvement on the ADCS-CGIC compared with 35.2% of the placebo group. The odds ratio (OR) for improvement on ADCS-CGIC for methylphenidate vs. placebo was 1.90 (P = .07).
There was also a strong association between score improvement on the NPI apathy subscale and improvement on the ADCS-CGIC subscale (OR, 2.95; P = .002).
“It is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition,” the researchers wrote.
In all, 17 serious adverse events occurred in the methylphenidate group and 10 occurred in the placebo group. However, all events were found to be hospitalizations for events not related to treatment.
‘Enduring effect’
Commenting on the findings, Jeffrey L. Cummings, MD, ScD, professor of brain sciences at the University of Nevada, Las Vegas, noted that the reduction in NPI apathy subscale score of more than 50% was clinically meaningful.
A more robust outcome on the ADCS-CGIC would have been desirable, he added, although that instrument is not designed specifically for apathy.
Methylphenidate’s effect on apathy observed at 2 months and remaining stable throughout the study makes it appear to be “an enduring effect, and not something that the patient accommodates to,” said Dr. Cummings, who was not involved with the research. Such a change may manifest itself in a patient’s greater willingness to help voluntarily with housework or to suggest going for a walk, he noted.
“These are not dramatic changes in cognition, of course, but they are changes in initiative and that is very important,” Dr. Cummings said. Decreased apathy also may improve quality of life for the patient’s caregiver, he added.
Overall, the findings raise the question of whether the Food and Drug Administration should recognize apathy as an indication for which drugs can be approved, said Dr. Cummings.
“For me, that would be the next major step in this line of investigation,” he concluded.
The study was funded by the National Institute on Aging. Dr. Mintzer has served as an adviser to Praxis Bioresearch and Cerevel Therapeutics on matters unrelated to this study. Dr. Cummings is the author of the Neuropsychiatric Inventory but does not receive payments for it from academic trials such as ADMET 2.
A version of this article first appeared on Medscape.com.
Methylphenidate is safe and effective for treating apathy in patients with Alzheimer’s disease (AD), new research suggests.
Results from a phase 3 randomized trial showed that, after 6 months of treatment, mean score on the Neuropsychiatric Inventory (NPI) apathy subscale decreased by 4.5 points for patients who received methylphenidate vs. a decrease of 3.1 points for those who received placebo.
In addition, the safety profile showed no significant between-group differences.
“Methylphenidate offers a treatment approach providing a modest but potentially clinically significant benefit for patients and caregivers,” said the investigators, led by Jacobo E. Mintzer, MD, MBA, professor of health studies at the Medical University of South Carolina in Charleston.
The findings were published online Sept. 27 in JAMA Neurology.
Common problem
Apathy, which is common among patients with AD, is associated with increased risk for mortality, financial burden, and caregiver burden. No treatment has proved effective for apathy in this population.
Two trials of methylphenidate, a catecholaminergic agent, have provided preliminary evidence of efficacy. Findings from the Apathy in Dementia Methylphenidate trial (ADMET) suggested the drug was associated with improved cognition and few adverse events. However, both trials had small patient populations and short durations.
The current investigators conducted ADMET 2, a 6-month, phase 3 trial, to investigate methylphenidate further. They recruited 200 patients (mean age, 76 years; 66% men; 90% White) at nine clinical centers that specialized in dementia care in the United States and one in Canada.
Eligible patients had a diagnosis of possible or probable AD and a Mini-Mental State Examination (MMSE) score between 10 and 28. They also had clinically significant apathy for at least 4 weeks and an available caregiver who spent more than 10 hours a week with the patient.
The researchers randomly assigned patients to receive methylphenidate (n = 99) or placebo (n = 101). For 3 days, participants in the active group received 10 mg/day of methylphenidate. After that point, they received 20 mg/day of methylphenidate for the rest of the study.
Patients in both treatment groups were given the same number of identical-appearing capsules each day.
In-person follow-up visits took place monthly for 6 months. Participants also were contacted by telephone at days 15, 45, and 75 after treatment assignment.
Participants underwent cognitive testing at baseline and at 2, 4, and 6 months. The battery of tests included the MMSE, Hopkins Verbal Learning Test, and Wechsler Adult Intelligence Scale – Revised Digit Span.
The trial’s two primary outcomes were mean change in NPI apathy score from baseline to 6 months and the odds of an improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC) between baseline and 6 months.
Significant change on either outcome was to be considered a signal of effective treatment.
Treatment-specific benefit
Ten patients in the methylphenidate group and seven in the placebo group withdrew during the study.
Mean baseline score on the NPI apathy subscale was 8.0 vs. 7.6, respectively.
In an adjusted, longitudinal model, mean between-group difference in change in NPI apathy score at 6 months was –1.25 (P = .002). The mean NPI apathy score decreased by 4.5 points in the methylphenidate group vs. 3.1 points in the placebo group.
The largest change in apathy score occurred during the first 2 months of treatment. At 6 months, 27% of the methylphenidate group vs. 14% of the placebo group had an NPI apathy score of 0.
In addition, 43.8% of the methylphenidate group had improvement on the ADCS-CGIC compared with 35.2% of the placebo group. The odds ratio (OR) for improvement on ADCS-CGIC for methylphenidate vs. placebo was 1.90 (P = .07).
There was also a strong association between score improvement on the NPI apathy subscale and improvement on the ADCS-CGIC subscale (OR, 2.95; P = .002).
“It is important to note that there were no group differences in any of the cognitive measures, suggesting that the effect of the treatment is specific to the treatment of apathy and not a secondary effect of improvement in cognition,” the researchers wrote.
In all, 17 serious adverse events occurred in the methylphenidate group and 10 occurred in the placebo group. However, all events were found to be hospitalizations for events not related to treatment.
‘Enduring effect’
Commenting on the findings, Jeffrey L. Cummings, MD, ScD, professor of brain sciences at the University of Nevada, Las Vegas, noted that the reduction in NPI apathy subscale score of more than 50% was clinically meaningful.
A more robust outcome on the ADCS-CGIC would have been desirable, he added, although that instrument is not designed specifically for apathy.
Methylphenidate’s effect on apathy observed at 2 months and remaining stable throughout the study makes it appear to be “an enduring effect, and not something that the patient accommodates to,” said Dr. Cummings, who was not involved with the research. Such a change may manifest itself in a patient’s greater willingness to help voluntarily with housework or to suggest going for a walk, he noted.
“These are not dramatic changes in cognition, of course, but they are changes in initiative and that is very important,” Dr. Cummings said. Decreased apathy also may improve quality of life for the patient’s caregiver, he added.
Overall, the findings raise the question of whether the Food and Drug Administration should recognize apathy as an indication for which drugs can be approved, said Dr. Cummings.
“For me, that would be the next major step in this line of investigation,” he concluded.
The study was funded by the National Institute on Aging. Dr. Mintzer has served as an adviser to Praxis Bioresearch and Cerevel Therapeutics on matters unrelated to this study. Dr. Cummings is the author of the Neuropsychiatric Inventory but does not receive payments for it from academic trials such as ADMET 2.
A version of this article first appeared on Medscape.com.
FDA okays new oral CGRP antagonist for migraine prevention
the manufacturer announced in a release.
The once-daily medication will be available in doses of 10 mg, 30 mg, and 60 mg.
“Qulipta provides a simple oral treatment option specifically developed to prevent migraine attacks and target CGRP, which is believed to be crucially involved in migraine in many patients,” coinvestigator Peter J. Goadsby, MD, PhD, DSc, neurologist and professor at the University of California, Los Angeles, and King’s College London, said in the release.
Approval was based partly on the findings from the phase 3 ADVANCE trial, in which patients with episodic migraine were randomly assigned to receive placebo or a 10-mg, 30-mg, or 60-mg daily dose of atogepant for 12 weeks.
As reported by this news organization, all three doses of atogepant reduced the number of mean monthly migraine days.
With this approval, neurologists will be able to choose from four monoclonal antibodies and two gepants for the preventive treatment of migraine.
“Having another gepant that can also be given preventively is a good idea, because one may be better than the other for a patient,” Alan M. Rapoport, MD, past president of the International Headache Society and founder and director emeritus of the New England Center for Headache, Stamford, Conn., told this news organization.
“Once we have a year or so of experience with atogepant, we’ll have a pretty good idea of which one works better preventively,” said Dr. Rapoport, who was not involved with the research.
Practice changing?
In the ADVANCE trial, there was a reduction of 3.69 migraine days with the 10-mg dose, 3.86 days with the 30-mg dose, and 4.2 days with the 60-mg dose. Placebo was associated with a reduction of 2.48 migraine days.
In addition, more than half of patients in each atogepant arm achieved a reduction in mean monthly migraine days of 50% or greater. This outcome occurred in 55.6% of the 10-mg atogepant group, 58.7% of the 30-mg group, and 60.8% of the 60-mg group. Approximately 29% patients who received placebo achieved this outcome.
The data indicated that atogepant has a favorable safety profile. The most common adverse events associated with treatment were constipation, nausea, and upper respiratory tract infection.
Dr. Rapoport, who is also a clinical professor of neurology at UCLA, noted that he was impressed with the efficacy.
“I’m not as impressed with the adverse events, but they’re not serious, and they don’t necessarily last,” he said.
Although being able to prescribe a single drug for acute and preventive treatment may be an advantage, it remains to be seen whether the tolerability and price of atogepant will be barriers for patients, Dr. Rapoport added.
How the approval will affect clinical practice is also unclear, he noted.
“If you’re going to start someone on a preventive, especially if it’s a woman of childbearing potential, you might just consider one of the two gepants. Doctors will decide once they see how they work,” said Dr. Rapoport.
Not a ‘breakthrough’ treatment
Also commenting ahead of the approval, Elizabeth W. Loder, MD, vice chair for academic affairs in the department of neurology at Brigham and Women’s Hospital, Boston, noted that the “safety of these CGRP medications in pregnancy is uncertain, and there are theoretical reasons to be concerned about it.”
Unlike injectable CGRP medications, atogepant is eliminated from the body relatively quickly after the patient stops taking it, said Dr. Loder, who is also professor of neurology at Harvard Medical School, Boston. However, atogepant may not otherwise differ greatly from other medications of its type.
“I don’t see a reason to think that one of these oral CGRP medicines is much more effective than another one,” said Dr. Loder.
“In my mind, as a clinician who will be prescribing these for patients, it will be cost and the ease of getting it covered that makes the difference,” she added.
These questions may raise concerns. “Those of us who treat patients who do not have private insurance find it very difficult to get these medications for them, even in situations where they have exhausted other alternatives,” said Dr. Loder.
Patients insured by Medicare or Medicaid “usually have no avenue to get some of these new, expensive treatments,” she said.
The approval of atogepant for acute and preventive treatment shows that the distinction between these indications may be artificial, Dr. Loder noted. The approval “will, I hope, help people think more flexibly about the way in which we use medications.”
It is a positive that atogepant has emerged as another option for preventive therapy, but the treatment cannot be considered a breakthrough, Dr. Loder added. The efficacy of atogepant, like that of other preventive treatments for migraine, is modest.
“It would be so nice if we could find things that were more effective than the treatments we currently have,” said Dr. Loder.
A version of this article first appeared on Medscape.com.
the manufacturer announced in a release.
The once-daily medication will be available in doses of 10 mg, 30 mg, and 60 mg.
“Qulipta provides a simple oral treatment option specifically developed to prevent migraine attacks and target CGRP, which is believed to be crucially involved in migraine in many patients,” coinvestigator Peter J. Goadsby, MD, PhD, DSc, neurologist and professor at the University of California, Los Angeles, and King’s College London, said in the release.
Approval was based partly on the findings from the phase 3 ADVANCE trial, in which patients with episodic migraine were randomly assigned to receive placebo or a 10-mg, 30-mg, or 60-mg daily dose of atogepant for 12 weeks.
As reported by this news organization, all three doses of atogepant reduced the number of mean monthly migraine days.
With this approval, neurologists will be able to choose from four monoclonal antibodies and two gepants for the preventive treatment of migraine.
“Having another gepant that can also be given preventively is a good idea, because one may be better than the other for a patient,” Alan M. Rapoport, MD, past president of the International Headache Society and founder and director emeritus of the New England Center for Headache, Stamford, Conn., told this news organization.
“Once we have a year or so of experience with atogepant, we’ll have a pretty good idea of which one works better preventively,” said Dr. Rapoport, who was not involved with the research.
Practice changing?
In the ADVANCE trial, there was a reduction of 3.69 migraine days with the 10-mg dose, 3.86 days with the 30-mg dose, and 4.2 days with the 60-mg dose. Placebo was associated with a reduction of 2.48 migraine days.
In addition, more than half of patients in each atogepant arm achieved a reduction in mean monthly migraine days of 50% or greater. This outcome occurred in 55.6% of the 10-mg atogepant group, 58.7% of the 30-mg group, and 60.8% of the 60-mg group. Approximately 29% patients who received placebo achieved this outcome.
The data indicated that atogepant has a favorable safety profile. The most common adverse events associated with treatment were constipation, nausea, and upper respiratory tract infection.
Dr. Rapoport, who is also a clinical professor of neurology at UCLA, noted that he was impressed with the efficacy.
“I’m not as impressed with the adverse events, but they’re not serious, and they don’t necessarily last,” he said.
Although being able to prescribe a single drug for acute and preventive treatment may be an advantage, it remains to be seen whether the tolerability and price of atogepant will be barriers for patients, Dr. Rapoport added.
How the approval will affect clinical practice is also unclear, he noted.
“If you’re going to start someone on a preventive, especially if it’s a woman of childbearing potential, you might just consider one of the two gepants. Doctors will decide once they see how they work,” said Dr. Rapoport.
Not a ‘breakthrough’ treatment
Also commenting ahead of the approval, Elizabeth W. Loder, MD, vice chair for academic affairs in the department of neurology at Brigham and Women’s Hospital, Boston, noted that the “safety of these CGRP medications in pregnancy is uncertain, and there are theoretical reasons to be concerned about it.”
Unlike injectable CGRP medications, atogepant is eliminated from the body relatively quickly after the patient stops taking it, said Dr. Loder, who is also professor of neurology at Harvard Medical School, Boston. However, atogepant may not otherwise differ greatly from other medications of its type.
“I don’t see a reason to think that one of these oral CGRP medicines is much more effective than another one,” said Dr. Loder.
“In my mind, as a clinician who will be prescribing these for patients, it will be cost and the ease of getting it covered that makes the difference,” she added.
These questions may raise concerns. “Those of us who treat patients who do not have private insurance find it very difficult to get these medications for them, even in situations where they have exhausted other alternatives,” said Dr. Loder.
Patients insured by Medicare or Medicaid “usually have no avenue to get some of these new, expensive treatments,” she said.
The approval of atogepant for acute and preventive treatment shows that the distinction between these indications may be artificial, Dr. Loder noted. The approval “will, I hope, help people think more flexibly about the way in which we use medications.”
It is a positive that atogepant has emerged as another option for preventive therapy, but the treatment cannot be considered a breakthrough, Dr. Loder added. The efficacy of atogepant, like that of other preventive treatments for migraine, is modest.
“It would be so nice if we could find things that were more effective than the treatments we currently have,” said Dr. Loder.
A version of this article first appeared on Medscape.com.
the manufacturer announced in a release.
The once-daily medication will be available in doses of 10 mg, 30 mg, and 60 mg.
“Qulipta provides a simple oral treatment option specifically developed to prevent migraine attacks and target CGRP, which is believed to be crucially involved in migraine in many patients,” coinvestigator Peter J. Goadsby, MD, PhD, DSc, neurologist and professor at the University of California, Los Angeles, and King’s College London, said in the release.
Approval was based partly on the findings from the phase 3 ADVANCE trial, in which patients with episodic migraine were randomly assigned to receive placebo or a 10-mg, 30-mg, or 60-mg daily dose of atogepant for 12 weeks.
As reported by this news organization, all three doses of atogepant reduced the number of mean monthly migraine days.
With this approval, neurologists will be able to choose from four monoclonal antibodies and two gepants for the preventive treatment of migraine.
“Having another gepant that can also be given preventively is a good idea, because one may be better than the other for a patient,” Alan M. Rapoport, MD, past president of the International Headache Society and founder and director emeritus of the New England Center for Headache, Stamford, Conn., told this news organization.
“Once we have a year or so of experience with atogepant, we’ll have a pretty good idea of which one works better preventively,” said Dr. Rapoport, who was not involved with the research.
Practice changing?
In the ADVANCE trial, there was a reduction of 3.69 migraine days with the 10-mg dose, 3.86 days with the 30-mg dose, and 4.2 days with the 60-mg dose. Placebo was associated with a reduction of 2.48 migraine days.
In addition, more than half of patients in each atogepant arm achieved a reduction in mean monthly migraine days of 50% or greater. This outcome occurred in 55.6% of the 10-mg atogepant group, 58.7% of the 30-mg group, and 60.8% of the 60-mg group. Approximately 29% patients who received placebo achieved this outcome.
The data indicated that atogepant has a favorable safety profile. The most common adverse events associated with treatment were constipation, nausea, and upper respiratory tract infection.
Dr. Rapoport, who is also a clinical professor of neurology at UCLA, noted that he was impressed with the efficacy.
“I’m not as impressed with the adverse events, but they’re not serious, and they don’t necessarily last,” he said.
Although being able to prescribe a single drug for acute and preventive treatment may be an advantage, it remains to be seen whether the tolerability and price of atogepant will be barriers for patients, Dr. Rapoport added.
How the approval will affect clinical practice is also unclear, he noted.
“If you’re going to start someone on a preventive, especially if it’s a woman of childbearing potential, you might just consider one of the two gepants. Doctors will decide once they see how they work,” said Dr. Rapoport.
Not a ‘breakthrough’ treatment
Also commenting ahead of the approval, Elizabeth W. Loder, MD, vice chair for academic affairs in the department of neurology at Brigham and Women’s Hospital, Boston, noted that the “safety of these CGRP medications in pregnancy is uncertain, and there are theoretical reasons to be concerned about it.”
Unlike injectable CGRP medications, atogepant is eliminated from the body relatively quickly after the patient stops taking it, said Dr. Loder, who is also professor of neurology at Harvard Medical School, Boston. However, atogepant may not otherwise differ greatly from other medications of its type.
“I don’t see a reason to think that one of these oral CGRP medicines is much more effective than another one,” said Dr. Loder.
“In my mind, as a clinician who will be prescribing these for patients, it will be cost and the ease of getting it covered that makes the difference,” she added.
These questions may raise concerns. “Those of us who treat patients who do not have private insurance find it very difficult to get these medications for them, even in situations where they have exhausted other alternatives,” said Dr. Loder.
Patients insured by Medicare or Medicaid “usually have no avenue to get some of these new, expensive treatments,” she said.
The approval of atogepant for acute and preventive treatment shows that the distinction between these indications may be artificial, Dr. Loder noted. The approval “will, I hope, help people think more flexibly about the way in which we use medications.”
It is a positive that atogepant has emerged as another option for preventive therapy, but the treatment cannot be considered a breakthrough, Dr. Loder added. The efficacy of atogepant, like that of other preventive treatments for migraine, is modest.
“It would be so nice if we could find things that were more effective than the treatments we currently have,” said Dr. Loder.
A version of this article first appeared on Medscape.com.
Aspirin and heparin increase bleeding risk during EVT
Treatment with acetylsalicylic acid (ASA) or heparin is associated with an increased risk for symptomatic intracranial hemorrhage (sICH) in patients with ischemic stroke who are undergoing endovascular therapy (EVT), new data show.
In this population, ASA and heparin are each associated with an approximately doubled risk for sICH when administered during EVT.
“We did not find any evidence for a beneficial effect on functional outcome,” investigator Wouter van der Steen, MD, research physician and PhD student at Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization. The possibility that a positive effect would be observed if the trial were continued was considered negligible, he added.
The researchers stopped the trial for safety reasons and recommend avoiding the evaluated dosages of both medications during EVT for ischemic stroke, said Dr. van der Steen.
He presented the findings from the MR CLEAN-MED trial at the European Stroke Organisation Conference (ESOC) 2021, which was held online.
Trial stopped for safety
Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery, the researchers note.
Microthrombi, which occlude distal vessels, and neutrophil extracellular traps can cause IMR. This problem can be reduced through treatment with ASA, which has an antithrombotic effect, or with heparin, which dissolves neutrophil extracellular traps, they add. Although these drugs are associated with good clinical outcomes, they entail an increased risk for sICH.
The investigators conducted the multicenter, randomized controlled MR CLEAN-MED trial to evaluate the effect of intravenous (IV) ASA and heparin, alone or in combination, during EVT for acute ischemic stroke. Treatment was open label, but outcome assessment was blinded. Eligible participants were adults with a National Institutes of Health Stroke Scale (NIHSS) score of greater than or equal to 2 and an anterior circulation large-vessel occlusion for whom EVT could be initiated in fewer than 6 hours.
Investigators randomly assigned patients to receive or not to receive ASA. Within each of these two treatment groups, patients were randomly assigned to receive no heparin, low-dose heparin, or moderate-dose heparin.
ASA was given in a loading dose of 300 mg. Patients who were given low-dose heparin received a loading dose of 5,000 IU followed by 500 IU/h for 6 hours. Patients who received moderate-dose heparin were given a loading dose of 5,000 IU followed by 1,250 IU/h for 6 hours.
The study’s primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were sICH and death within 90 days.
An independent, unblinded data and safety monitoring board (DSMB) assessed the risk for the primary safety outcomes throughout the trial. The board performed interim analyses of safety and efficacy for every 300 patients.
After the fourth safety assessment, the DSMB recommended that enrollment in the moderate-dose heparin arm be discontinued for safety reasons. Enrollment in other arms continued.
After the second interim analysis, the DSMB advised that the trial steering committee be unblinded to decide whether to stop or continue the trial. The steering committee decided to stop the trial for reasons of safety.
Increased risk for sICH
In all, 628 patients were included in the study. The ASA groups included 310 patients, and the no-ASA groups included 318 patients. In all, 332 participants received heparin, and 296 received no heparin.
The demographic characteristics were well balanced between groups. The population’s median age was 73 years, and about 53% were men. The median baseline NIHSS score was approximately 15. About 74% of patients received IV thrombolysis. The median baseline Alberta Stroke Program Early CT Scan score was 9.
The investigators observed a slight shift toward worse outcome in the ASA group, compared with the no-ASA group (adjusted OR, 0.91). In addition, the ASA group had a significantly increased risk for sICH, compared with the no-ASA group (14% vs. 7.2%; aOR, 1.95).
Patients in the ASA group were less likely to have good functional outcome (mRS of 0 to 2; aOR, 0.76), and the mortality rate tended to be higher.
The researchers found a nonsignificant shift toward a worse functional outcome in the heparin group, compared with the no-heparin group (aOR, 0.81). The risk for sICH was significantly higher in the heparin group, compared with the no-heparin group (13% vs. 7.4%; aOR, 2.00).
Patients in the heparin group were also less likely to have a good functional outcome (aOR, 0.78), and there was a nonsignificant increase in risk for death among those patients.
The rate of sICH was 11% in the group that received low-dose heparin; it was 26% in the group that received moderate-dose heparin (aOR, 6.05). The mortality rate was 23% in the low-dose group and 47% in the moderate-dose group (aOR, 5.45).
There was no significant interaction between ASA and heparin on the primary outcome and on sICH occurrence.
‘A unique trial’
“MR CLEAN-MED is a unique trial because it investigated a widely used treatment but until now without any proof of effectiveness,” said Dr. van der Steen. The researchers expect that their findings will have a strong impact on the management of patients with acute ischemic stroke. They suggest that the administration of antithrombotic agents during EVT be avoided.
“We consider it probable that the increased risk of sICH explains at least a part of the nonsignificant shift towards a worse functional outcome,” co-investigator Bob Roozenbeek, MD, PhD, a neurologist at the Erasmus Medical Center, said in an interview. “However, to make more definite statements, we will have to do more in-depth analyses.”
It remains unclear whether the periprocedural use of lower dosages of antithrombotic agents or of a single bolus of heparin could be safe and effective, said Dr. van der Steen.
To gain insight into these questions, the investigators will evaluate the effect of the medications and dosages examined in this trial on primary hemostasis and coagulation activity in the trial population. They also plan to examine the effect of primary hemostasis and coagulation activity on risk for sICH and functional outcome.
Enhancing the effectiveness of thrombectomy for acute ischemic stroke continues to be an important goal for stroke therapy, said Mark Fisher, MD, professor of neurology and pathology and laboratory medicine at the University of California, Irvine, who commented on the findings for this news organization.
At least three strategies are available: The use of ancillary antithrombotic medications, neuroprotection, and modulation of the vasoconstrictive properties of the microcirculation.
“Results of MR CLEAN-MED argue against the antithrombotic strategy,” said Dr. Fisher. “The alternate strategies remain viable, and results of interventions using those approaches are awaited with great interest.”
The study was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative and the Brain Foundation Netherlands. Funding also was provided by Stryker, Medtronic, and Cerenovus. Dr. van der Steen and Dr. Fisher have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Treatment with acetylsalicylic acid (ASA) or heparin is associated with an increased risk for symptomatic intracranial hemorrhage (sICH) in patients with ischemic stroke who are undergoing endovascular therapy (EVT), new data show.
In this population, ASA and heparin are each associated with an approximately doubled risk for sICH when administered during EVT.
“We did not find any evidence for a beneficial effect on functional outcome,” investigator Wouter van der Steen, MD, research physician and PhD student at Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization. The possibility that a positive effect would be observed if the trial were continued was considered negligible, he added.
The researchers stopped the trial for safety reasons and recommend avoiding the evaluated dosages of both medications during EVT for ischemic stroke, said Dr. van der Steen.
He presented the findings from the MR CLEAN-MED trial at the European Stroke Organisation Conference (ESOC) 2021, which was held online.
Trial stopped for safety
Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery, the researchers note.
Microthrombi, which occlude distal vessels, and neutrophil extracellular traps can cause IMR. This problem can be reduced through treatment with ASA, which has an antithrombotic effect, or with heparin, which dissolves neutrophil extracellular traps, they add. Although these drugs are associated with good clinical outcomes, they entail an increased risk for sICH.
The investigators conducted the multicenter, randomized controlled MR CLEAN-MED trial to evaluate the effect of intravenous (IV) ASA and heparin, alone or in combination, during EVT for acute ischemic stroke. Treatment was open label, but outcome assessment was blinded. Eligible participants were adults with a National Institutes of Health Stroke Scale (NIHSS) score of greater than or equal to 2 and an anterior circulation large-vessel occlusion for whom EVT could be initiated in fewer than 6 hours.
Investigators randomly assigned patients to receive or not to receive ASA. Within each of these two treatment groups, patients were randomly assigned to receive no heparin, low-dose heparin, or moderate-dose heparin.
ASA was given in a loading dose of 300 mg. Patients who were given low-dose heparin received a loading dose of 5,000 IU followed by 500 IU/h for 6 hours. Patients who received moderate-dose heparin were given a loading dose of 5,000 IU followed by 1,250 IU/h for 6 hours.
The study’s primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were sICH and death within 90 days.
An independent, unblinded data and safety monitoring board (DSMB) assessed the risk for the primary safety outcomes throughout the trial. The board performed interim analyses of safety and efficacy for every 300 patients.
After the fourth safety assessment, the DSMB recommended that enrollment in the moderate-dose heparin arm be discontinued for safety reasons. Enrollment in other arms continued.
After the second interim analysis, the DSMB advised that the trial steering committee be unblinded to decide whether to stop or continue the trial. The steering committee decided to stop the trial for reasons of safety.
Increased risk for sICH
In all, 628 patients were included in the study. The ASA groups included 310 patients, and the no-ASA groups included 318 patients. In all, 332 participants received heparin, and 296 received no heparin.
The demographic characteristics were well balanced between groups. The population’s median age was 73 years, and about 53% were men. The median baseline NIHSS score was approximately 15. About 74% of patients received IV thrombolysis. The median baseline Alberta Stroke Program Early CT Scan score was 9.
The investigators observed a slight shift toward worse outcome in the ASA group, compared with the no-ASA group (adjusted OR, 0.91). In addition, the ASA group had a significantly increased risk for sICH, compared with the no-ASA group (14% vs. 7.2%; aOR, 1.95).
Patients in the ASA group were less likely to have good functional outcome (mRS of 0 to 2; aOR, 0.76), and the mortality rate tended to be higher.
The researchers found a nonsignificant shift toward a worse functional outcome in the heparin group, compared with the no-heparin group (aOR, 0.81). The risk for sICH was significantly higher in the heparin group, compared with the no-heparin group (13% vs. 7.4%; aOR, 2.00).
Patients in the heparin group were also less likely to have a good functional outcome (aOR, 0.78), and there was a nonsignificant increase in risk for death among those patients.
The rate of sICH was 11% in the group that received low-dose heparin; it was 26% in the group that received moderate-dose heparin (aOR, 6.05). The mortality rate was 23% in the low-dose group and 47% in the moderate-dose group (aOR, 5.45).
There was no significant interaction between ASA and heparin on the primary outcome and on sICH occurrence.
‘A unique trial’
“MR CLEAN-MED is a unique trial because it investigated a widely used treatment but until now without any proof of effectiveness,” said Dr. van der Steen. The researchers expect that their findings will have a strong impact on the management of patients with acute ischemic stroke. They suggest that the administration of antithrombotic agents during EVT be avoided.
“We consider it probable that the increased risk of sICH explains at least a part of the nonsignificant shift towards a worse functional outcome,” co-investigator Bob Roozenbeek, MD, PhD, a neurologist at the Erasmus Medical Center, said in an interview. “However, to make more definite statements, we will have to do more in-depth analyses.”
It remains unclear whether the periprocedural use of lower dosages of antithrombotic agents or of a single bolus of heparin could be safe and effective, said Dr. van der Steen.
To gain insight into these questions, the investigators will evaluate the effect of the medications and dosages examined in this trial on primary hemostasis and coagulation activity in the trial population. They also plan to examine the effect of primary hemostasis and coagulation activity on risk for sICH and functional outcome.
Enhancing the effectiveness of thrombectomy for acute ischemic stroke continues to be an important goal for stroke therapy, said Mark Fisher, MD, professor of neurology and pathology and laboratory medicine at the University of California, Irvine, who commented on the findings for this news organization.
At least three strategies are available: The use of ancillary antithrombotic medications, neuroprotection, and modulation of the vasoconstrictive properties of the microcirculation.
“Results of MR CLEAN-MED argue against the antithrombotic strategy,” said Dr. Fisher. “The alternate strategies remain viable, and results of interventions using those approaches are awaited with great interest.”
The study was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative and the Brain Foundation Netherlands. Funding also was provided by Stryker, Medtronic, and Cerenovus. Dr. van der Steen and Dr. Fisher have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Treatment with acetylsalicylic acid (ASA) or heparin is associated with an increased risk for symptomatic intracranial hemorrhage (sICH) in patients with ischemic stroke who are undergoing endovascular therapy (EVT), new data show.
In this population, ASA and heparin are each associated with an approximately doubled risk for sICH when administered during EVT.
“We did not find any evidence for a beneficial effect on functional outcome,” investigator Wouter van der Steen, MD, research physician and PhD student at Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization. The possibility that a positive effect would be observed if the trial were continued was considered negligible, he added.
The researchers stopped the trial for safety reasons and recommend avoiding the evaluated dosages of both medications during EVT for ischemic stroke, said Dr. van der Steen.
He presented the findings from the MR CLEAN-MED trial at the European Stroke Organisation Conference (ESOC) 2021, which was held online.
Trial stopped for safety
Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery, the researchers note.
Microthrombi, which occlude distal vessels, and neutrophil extracellular traps can cause IMR. This problem can be reduced through treatment with ASA, which has an antithrombotic effect, or with heparin, which dissolves neutrophil extracellular traps, they add. Although these drugs are associated with good clinical outcomes, they entail an increased risk for sICH.
The investigators conducted the multicenter, randomized controlled MR CLEAN-MED trial to evaluate the effect of intravenous (IV) ASA and heparin, alone or in combination, during EVT for acute ischemic stroke. Treatment was open label, but outcome assessment was blinded. Eligible participants were adults with a National Institutes of Health Stroke Scale (NIHSS) score of greater than or equal to 2 and an anterior circulation large-vessel occlusion for whom EVT could be initiated in fewer than 6 hours.
Investigators randomly assigned patients to receive or not to receive ASA. Within each of these two treatment groups, patients were randomly assigned to receive no heparin, low-dose heparin, or moderate-dose heparin.
ASA was given in a loading dose of 300 mg. Patients who were given low-dose heparin received a loading dose of 5,000 IU followed by 500 IU/h for 6 hours. Patients who received moderate-dose heparin were given a loading dose of 5,000 IU followed by 1,250 IU/h for 6 hours.
The study’s primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were sICH and death within 90 days.
An independent, unblinded data and safety monitoring board (DSMB) assessed the risk for the primary safety outcomes throughout the trial. The board performed interim analyses of safety and efficacy for every 300 patients.
After the fourth safety assessment, the DSMB recommended that enrollment in the moderate-dose heparin arm be discontinued for safety reasons. Enrollment in other arms continued.
After the second interim analysis, the DSMB advised that the trial steering committee be unblinded to decide whether to stop or continue the trial. The steering committee decided to stop the trial for reasons of safety.
Increased risk for sICH
In all, 628 patients were included in the study. The ASA groups included 310 patients, and the no-ASA groups included 318 patients. In all, 332 participants received heparin, and 296 received no heparin.
The demographic characteristics were well balanced between groups. The population’s median age was 73 years, and about 53% were men. The median baseline NIHSS score was approximately 15. About 74% of patients received IV thrombolysis. The median baseline Alberta Stroke Program Early CT Scan score was 9.
The investigators observed a slight shift toward worse outcome in the ASA group, compared with the no-ASA group (adjusted OR, 0.91). In addition, the ASA group had a significantly increased risk for sICH, compared with the no-ASA group (14% vs. 7.2%; aOR, 1.95).
Patients in the ASA group were less likely to have good functional outcome (mRS of 0 to 2; aOR, 0.76), and the mortality rate tended to be higher.
The researchers found a nonsignificant shift toward a worse functional outcome in the heparin group, compared with the no-heparin group (aOR, 0.81). The risk for sICH was significantly higher in the heparin group, compared with the no-heparin group (13% vs. 7.4%; aOR, 2.00).
Patients in the heparin group were also less likely to have a good functional outcome (aOR, 0.78), and there was a nonsignificant increase in risk for death among those patients.
The rate of sICH was 11% in the group that received low-dose heparin; it was 26% in the group that received moderate-dose heparin (aOR, 6.05). The mortality rate was 23% in the low-dose group and 47% in the moderate-dose group (aOR, 5.45).
There was no significant interaction between ASA and heparin on the primary outcome and on sICH occurrence.
‘A unique trial’
“MR CLEAN-MED is a unique trial because it investigated a widely used treatment but until now without any proof of effectiveness,” said Dr. van der Steen. The researchers expect that their findings will have a strong impact on the management of patients with acute ischemic stroke. They suggest that the administration of antithrombotic agents during EVT be avoided.
“We consider it probable that the increased risk of sICH explains at least a part of the nonsignificant shift towards a worse functional outcome,” co-investigator Bob Roozenbeek, MD, PhD, a neurologist at the Erasmus Medical Center, said in an interview. “However, to make more definite statements, we will have to do more in-depth analyses.”
It remains unclear whether the periprocedural use of lower dosages of antithrombotic agents or of a single bolus of heparin could be safe and effective, said Dr. van der Steen.
To gain insight into these questions, the investigators will evaluate the effect of the medications and dosages examined in this trial on primary hemostasis and coagulation activity in the trial population. They also plan to examine the effect of primary hemostasis and coagulation activity on risk for sICH and functional outcome.
Enhancing the effectiveness of thrombectomy for acute ischemic stroke continues to be an important goal for stroke therapy, said Mark Fisher, MD, professor of neurology and pathology and laboratory medicine at the University of California, Irvine, who commented on the findings for this news organization.
At least three strategies are available: The use of ancillary antithrombotic medications, neuroprotection, and modulation of the vasoconstrictive properties of the microcirculation.
“Results of MR CLEAN-MED argue against the antithrombotic strategy,” said Dr. Fisher. “The alternate strategies remain viable, and results of interventions using those approaches are awaited with great interest.”
The study was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative and the Brain Foundation Netherlands. Funding also was provided by Stryker, Medtronic, and Cerenovus. Dr. van der Steen and Dr. Fisher have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Tranexamic acid fails to prevent ICH growth: TRAIGE trial results
(ICH), a new study shows.
In the randomized controlled trial, the rate of hematoma expansion was 40.4% among patients who received tranexamic acid and 41.5% among those who received placebo. The degree of disability at 90 days also did not differ between treatment arms.
“Our work has once again shown that tranexamic acid is safe in spontaneous ICH,” said Jingyi Liu, MD, a physician in the neurocritical care unit at Beijing Tiantan Hospital, Capital Medical University, Beijing. “Larger studies with more specified population are needed to further assess safety and efficacy of tranexamic acid in patients with ICH.”
The findings of the TRAIGE study were presented at the virtual European Stroke Organization Conference (ESOC) 2021. They were also published online June 28 in Stroke and Vascular Neurology.
Imaging-based patient selection
ICH is often fatal and entails a high risk for disability, the researchers wrote. Approximately 40% of patients with ICH die within a month of onset, and about two-thirds of patients do not achieve long-term functional independence.
Intracerebral hematoma expansion is predictive of poor clinical outcome in ICH. Data indicate that tranexamic acid, an antifibrinolytic agent, reduces hematoma expansion. But evidence of a clinical benefit of tranexamic acid has been elusive, they noted.
This lack of observed benefit may result from the inappropriate selection of research participants. The emergence of imaging biomarkers may help address this potential problem. In recent years, the blend sign and the black hole sign on noncontrast CT, as well as the spot sign on CT angiography, have been associated with higher risk for hematoma expansion and worse clinical outcome, the researchers wrote.
Between January 2015 and March 2020, the investigators enrolled consecutive patients with acute primary spontaneous ICH into their prospective study. Eligible patients presented at any of 10 stroke centers in China. They had the spot sign, blend sign, or black hole sign at admission and were able to receive treatment within 8 hours of onset.
The investigators randomly assigned patients in equal groups to receive placebo (0.9% NaCl) or tranexamic acid. Patients and study investigators were blinded to treatment assignment. Treatment was administered as an intravenous infusion over 8 hours.
The study’s primary endpoint was intracerebral hematoma expansion by 24 hours after start of treatment. Expansion was defined as an increase of > 6 mL or a growth of > 33% from baseline. Secondary endpoints included poor clinical outcome, defined as a Modified Rankin Scale (mRS) score of 4-6, and all-cause mortality, both at 90 days.
No differences in disability
The investigators enrolled 171 patients in their study; 24-hour CT images were available for 169 of them. Follow-up data at 90 days were available for 164 patients. The mean age of the patients was 55.9 years, and 72.5% of participants were men. At baseline, the mean ICH volume was 23.7 mL, and the median hematoma volume was 19.8 mL.
All patients received treatment within 8 hours. Hematoma expansion occurred in 40.9% of patients overall; 34.9% had a poor clinical outcome.
The investigators found no significant difference between treatment arms in the rate of hematoma expansion. This outcome occurred in 40.4% of the tranexamic acid group and 41.5% of the placebo group (odds ratio, 0.96; P = .89).
In addition, the researchers found no significant difference in the distribution of mRS scores at day 90 (P = .70). The rate of all-cause mortality at 90 days was lower in the tranexamic acid group (8.1%) than in the control group (10.0%), but this difference was not statistically significant (P = .71).
Potential clotting risk
One reason for the lack of observed benefit with tranexamic acid may be an inappropriate sample size, said Dr. Liu. Patient recruitment was difficult, especially in centers that used the spot sign as an inclusion criterion.
“We think a positive result could be seen in a substantially larger sample size,” said Dr. Liu. “Furthermore, we infer from our subgroup analysis that a more specified patient selection and shorter treatment window may be required for better effect.”
In some of their subgroup analyses, the researchers found a trend toward an increased effect in patients with moderate-size hematoma who received treatment in an earlier window. “That could be the targeted population for future studies,” said Dr. Liu. “We are working on further analysis of the population and possibly international collaboration.”
But tranexamic acid also entails risks, said Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, who provided independent commentary on the findings. “Tranexamic acid works on the thrombolytic system, so it increases clotting, and it does have a risk in people who are older and have risk factors for coronary disease and pulmonary embolism.”
As in ischemic stroke, time to treatment is a crucial consideration. Patients with ICH may receive treatment within 5 or 6 hours of onset, but most hemorrhages have reached their maximum size at that point. “The number of people that you can actually help by reducing the size is small,” said Dr. Caplan. “And then reducing the size in most hemorrhages doesn’t make any clinical difference.”
Stereotactic drainage, in which fluid is physically removed, is more likely to lead to long-term improvement for some patients with hemorrhage than limiting expansion, said Dr. Caplan. “That seems to be a more promising therapy,” he added.
The study was supported by the National Key R&D program of China, the National Natural Science Foundation of China, and the Beijing Science and Technology Commission. Dr. Liu and Dr. Caplan have disclosed no relevant financial relationshps.
A version of this article first appeared on Medscape.com.
(ICH), a new study shows.
In the randomized controlled trial, the rate of hematoma expansion was 40.4% among patients who received tranexamic acid and 41.5% among those who received placebo. The degree of disability at 90 days also did not differ between treatment arms.
“Our work has once again shown that tranexamic acid is safe in spontaneous ICH,” said Jingyi Liu, MD, a physician in the neurocritical care unit at Beijing Tiantan Hospital, Capital Medical University, Beijing. “Larger studies with more specified population are needed to further assess safety and efficacy of tranexamic acid in patients with ICH.”
The findings of the TRAIGE study were presented at the virtual European Stroke Organization Conference (ESOC) 2021. They were also published online June 28 in Stroke and Vascular Neurology.
Imaging-based patient selection
ICH is often fatal and entails a high risk for disability, the researchers wrote. Approximately 40% of patients with ICH die within a month of onset, and about two-thirds of patients do not achieve long-term functional independence.
Intracerebral hematoma expansion is predictive of poor clinical outcome in ICH. Data indicate that tranexamic acid, an antifibrinolytic agent, reduces hematoma expansion. But evidence of a clinical benefit of tranexamic acid has been elusive, they noted.
This lack of observed benefit may result from the inappropriate selection of research participants. The emergence of imaging biomarkers may help address this potential problem. In recent years, the blend sign and the black hole sign on noncontrast CT, as well as the spot sign on CT angiography, have been associated with higher risk for hematoma expansion and worse clinical outcome, the researchers wrote.
Between January 2015 and March 2020, the investigators enrolled consecutive patients with acute primary spontaneous ICH into their prospective study. Eligible patients presented at any of 10 stroke centers in China. They had the spot sign, blend sign, or black hole sign at admission and were able to receive treatment within 8 hours of onset.
The investigators randomly assigned patients in equal groups to receive placebo (0.9% NaCl) or tranexamic acid. Patients and study investigators were blinded to treatment assignment. Treatment was administered as an intravenous infusion over 8 hours.
The study’s primary endpoint was intracerebral hematoma expansion by 24 hours after start of treatment. Expansion was defined as an increase of > 6 mL or a growth of > 33% from baseline. Secondary endpoints included poor clinical outcome, defined as a Modified Rankin Scale (mRS) score of 4-6, and all-cause mortality, both at 90 days.
No differences in disability
The investigators enrolled 171 patients in their study; 24-hour CT images were available for 169 of them. Follow-up data at 90 days were available for 164 patients. The mean age of the patients was 55.9 years, and 72.5% of participants were men. At baseline, the mean ICH volume was 23.7 mL, and the median hematoma volume was 19.8 mL.
All patients received treatment within 8 hours. Hematoma expansion occurred in 40.9% of patients overall; 34.9% had a poor clinical outcome.
The investigators found no significant difference between treatment arms in the rate of hematoma expansion. This outcome occurred in 40.4% of the tranexamic acid group and 41.5% of the placebo group (odds ratio, 0.96; P = .89).
In addition, the researchers found no significant difference in the distribution of mRS scores at day 90 (P = .70). The rate of all-cause mortality at 90 days was lower in the tranexamic acid group (8.1%) than in the control group (10.0%), but this difference was not statistically significant (P = .71).
Potential clotting risk
One reason for the lack of observed benefit with tranexamic acid may be an inappropriate sample size, said Dr. Liu. Patient recruitment was difficult, especially in centers that used the spot sign as an inclusion criterion.
“We think a positive result could be seen in a substantially larger sample size,” said Dr. Liu. “Furthermore, we infer from our subgroup analysis that a more specified patient selection and shorter treatment window may be required for better effect.”
In some of their subgroup analyses, the researchers found a trend toward an increased effect in patients with moderate-size hematoma who received treatment in an earlier window. “That could be the targeted population for future studies,” said Dr. Liu. “We are working on further analysis of the population and possibly international collaboration.”
But tranexamic acid also entails risks, said Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, who provided independent commentary on the findings. “Tranexamic acid works on the thrombolytic system, so it increases clotting, and it does have a risk in people who are older and have risk factors for coronary disease and pulmonary embolism.”
As in ischemic stroke, time to treatment is a crucial consideration. Patients with ICH may receive treatment within 5 or 6 hours of onset, but most hemorrhages have reached their maximum size at that point. “The number of people that you can actually help by reducing the size is small,” said Dr. Caplan. “And then reducing the size in most hemorrhages doesn’t make any clinical difference.”
Stereotactic drainage, in which fluid is physically removed, is more likely to lead to long-term improvement for some patients with hemorrhage than limiting expansion, said Dr. Caplan. “That seems to be a more promising therapy,” he added.
The study was supported by the National Key R&D program of China, the National Natural Science Foundation of China, and the Beijing Science and Technology Commission. Dr. Liu and Dr. Caplan have disclosed no relevant financial relationshps.
A version of this article first appeared on Medscape.com.
(ICH), a new study shows.
In the randomized controlled trial, the rate of hematoma expansion was 40.4% among patients who received tranexamic acid and 41.5% among those who received placebo. The degree of disability at 90 days also did not differ between treatment arms.
“Our work has once again shown that tranexamic acid is safe in spontaneous ICH,” said Jingyi Liu, MD, a physician in the neurocritical care unit at Beijing Tiantan Hospital, Capital Medical University, Beijing. “Larger studies with more specified population are needed to further assess safety and efficacy of tranexamic acid in patients with ICH.”
The findings of the TRAIGE study were presented at the virtual European Stroke Organization Conference (ESOC) 2021. They were also published online June 28 in Stroke and Vascular Neurology.
Imaging-based patient selection
ICH is often fatal and entails a high risk for disability, the researchers wrote. Approximately 40% of patients with ICH die within a month of onset, and about two-thirds of patients do not achieve long-term functional independence.
Intracerebral hematoma expansion is predictive of poor clinical outcome in ICH. Data indicate that tranexamic acid, an antifibrinolytic agent, reduces hematoma expansion. But evidence of a clinical benefit of tranexamic acid has been elusive, they noted.
This lack of observed benefit may result from the inappropriate selection of research participants. The emergence of imaging biomarkers may help address this potential problem. In recent years, the blend sign and the black hole sign on noncontrast CT, as well as the spot sign on CT angiography, have been associated with higher risk for hematoma expansion and worse clinical outcome, the researchers wrote.
Between January 2015 and March 2020, the investigators enrolled consecutive patients with acute primary spontaneous ICH into their prospective study. Eligible patients presented at any of 10 stroke centers in China. They had the spot sign, blend sign, or black hole sign at admission and were able to receive treatment within 8 hours of onset.
The investigators randomly assigned patients in equal groups to receive placebo (0.9% NaCl) or tranexamic acid. Patients and study investigators were blinded to treatment assignment. Treatment was administered as an intravenous infusion over 8 hours.
The study’s primary endpoint was intracerebral hematoma expansion by 24 hours after start of treatment. Expansion was defined as an increase of > 6 mL or a growth of > 33% from baseline. Secondary endpoints included poor clinical outcome, defined as a Modified Rankin Scale (mRS) score of 4-6, and all-cause mortality, both at 90 days.
No differences in disability
The investigators enrolled 171 patients in their study; 24-hour CT images were available for 169 of them. Follow-up data at 90 days were available for 164 patients. The mean age of the patients was 55.9 years, and 72.5% of participants were men. At baseline, the mean ICH volume was 23.7 mL, and the median hematoma volume was 19.8 mL.
All patients received treatment within 8 hours. Hematoma expansion occurred in 40.9% of patients overall; 34.9% had a poor clinical outcome.
The investigators found no significant difference between treatment arms in the rate of hematoma expansion. This outcome occurred in 40.4% of the tranexamic acid group and 41.5% of the placebo group (odds ratio, 0.96; P = .89).
In addition, the researchers found no significant difference in the distribution of mRS scores at day 90 (P = .70). The rate of all-cause mortality at 90 days was lower in the tranexamic acid group (8.1%) than in the control group (10.0%), but this difference was not statistically significant (P = .71).
Potential clotting risk
One reason for the lack of observed benefit with tranexamic acid may be an inappropriate sample size, said Dr. Liu. Patient recruitment was difficult, especially in centers that used the spot sign as an inclusion criterion.
“We think a positive result could be seen in a substantially larger sample size,” said Dr. Liu. “Furthermore, we infer from our subgroup analysis that a more specified patient selection and shorter treatment window may be required for better effect.”
In some of their subgroup analyses, the researchers found a trend toward an increased effect in patients with moderate-size hematoma who received treatment in an earlier window. “That could be the targeted population for future studies,” said Dr. Liu. “We are working on further analysis of the population and possibly international collaboration.”
But tranexamic acid also entails risks, said Louis R. Caplan, MD, professor of neurology at Harvard Medical School, Boston, who provided independent commentary on the findings. “Tranexamic acid works on the thrombolytic system, so it increases clotting, and it does have a risk in people who are older and have risk factors for coronary disease and pulmonary embolism.”
As in ischemic stroke, time to treatment is a crucial consideration. Patients with ICH may receive treatment within 5 or 6 hours of onset, but most hemorrhages have reached their maximum size at that point. “The number of people that you can actually help by reducing the size is small,” said Dr. Caplan. “And then reducing the size in most hemorrhages doesn’t make any clinical difference.”
Stereotactic drainage, in which fluid is physically removed, is more likely to lead to long-term improvement for some patients with hemorrhage than limiting expansion, said Dr. Caplan. “That seems to be a more promising therapy,” he added.
The study was supported by the National Key R&D program of China, the National Natural Science Foundation of China, and the Beijing Science and Technology Commission. Dr. Liu and Dr. Caplan have disclosed no relevant financial relationshps.
A version of this article first appeared on Medscape.com.
FROM ESOC 2021
Number of global deaths by suicide increased over 30 years
The overall global number of deaths by suicide increased by almost 20,000 during the past 30 years, new research shows.
The increase occurred despite a significant decrease in age-specific suicide rates from 1990 through 2019, according to data from the Global Burden of Disease Study 2019.
Population growth, population aging, and changes in population age structure may explain the increase in number of suicide deaths, the investigators note.
“As suicide rates are highest among the elderly (70 years or above) for both genders in almost all regions of the world, the rapidly aging population globally will pose huge challenges for the reduction in the number of suicide deaths in the future,” write the researchers, led by Paul Siu Fai Yip, PhD, of the HKJC Center for Suicide Research and Prevention, University of Hong Kong, China.
The findings were published online Aug. 16 in Injury Prevention.
Global public health concern
Around the world, approximately 800,000 individuals die by suicide each year, while many others attempt suicide. Yet suicide has not received the same level of attention as other global public health concerns, such as HIV/AIDS and cancer, the investigators write.
They examined data from the Global Burden of Disease Study 2019 to assess how demographic and epidemiologic factors contributed to the number of suicide deaths during the past 30 years.
The researchers also analyzed relationships between population growth, population age structure, income level, and gender- and age-specific suicide rates.
The Global Burden of Disease Study 2019 includes information from 204 countries about 369 diseases and injuries by age and gender. The dataset also includes population estimates for each year by location, age group, and gender.
In their analysis, the investigators looked at changes in suicide rates and the number of suicide deaths from 1990 to 2019 by gender and age group in the four income level regions defined by the World Bank. These categories include low-income, lower-middle–income, upper-middle–income, and high-income regions.
Number of deaths versus suicide rates
The number of deaths was 738,799 in 1990 and 758,696 in 2019.
The largest increase in deaths occurred in the lower-middle–income region, where the number of suicide deaths increased by 72,550 (from 232,340 to 304,890).
Population growth (300,942; 1,512.5%) was the major contributor to the overall increase in total number of suicide deaths. The second largest contributor was population age structure (189,512; 952.4%).
However, the effects of these factors were offset to a large extent by the effect of reduction in overall suicide rates (−470,556; −2,364.9%).
Interestingly, the overall suicide rate per 100,000 population decreased from 13.8 in 1990 to 9.8 in 2019.
The upper-middle–income region had the largest decline (−6.25 per 100,000), and the high-income region had the smallest decline (−1.77 per 100,000). Suicide rates also decreased in lower-middle–income (−2.51 per 100,000) and low-income regions (−1.96 per 100,000).
Reasons for the declines across all regions “have yet to be determined,” write the investigators. International efforts coordinated by the United Nations and World Health Organization likely contributed to these declines, they add.
‘Imbalance of resources’
The overall reduction in suicide rate of −4.01 per 100,000 “was mainly due” to reduction in age-specific suicide rates (−6.09; 152%), the researchers report.
This effect was partly offset, however, by the effect of the changing population age structure (2.08; −52%). In the high-income–level region, for example, the reduction in age-specific suicide rate (−3.83; 216.3%) was greater than the increase resulting from the change in population age structure (2.06; −116.3%).
“The overall contribution of population age structure mainly came from the 45-64 (565.2%) and 65+ (528.7%) age groups,” the investigators write. “This effect was observed in middle-income– as well as high-income–level regions, reflecting the global effect of population aging.”
They add that world populations will “experience pronounced and historically unprecedented aging in the coming decades” because of increasing life expectancy and declining fertility.
Men, but not women, had a notable increase in total number of suicide deaths. The significant effect of male population growth (177,128; 890.2% vs. 123,814; 622.3% for women) and male population age structure (120,186; 604.0% vs. 69,325; 348.4%) were the main factors that explained this increase, the investigators note.
However, from 1990 to 2019, the overall suicide rate per 100,000 men decreased from 16.6 to 13.5 (–3.09). The decline in overall suicide rate was even greater for women, from 11.0 to 6.1 (–4.91).
This finding was particularly notable in the upper-middle–income region (–8.12 women vs. –4.37 men per 100,000).
“This study highlighted the considerable imbalance of the resources in carrying out suicide prevention work, especially in low-income and middle-income countries,” the investigators write.
“It is time to revisit this situation to ensure that sufficient resources can be redeployed globally to meet the future challenges,” they add.
The study was funded by a Humanities and Social Sciences Prestigious Fellowship, which Dr. Yip received. He declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The overall global number of deaths by suicide increased by almost 20,000 during the past 30 years, new research shows.
The increase occurred despite a significant decrease in age-specific suicide rates from 1990 through 2019, according to data from the Global Burden of Disease Study 2019.
Population growth, population aging, and changes in population age structure may explain the increase in number of suicide deaths, the investigators note.
“As suicide rates are highest among the elderly (70 years or above) for both genders in almost all regions of the world, the rapidly aging population globally will pose huge challenges for the reduction in the number of suicide deaths in the future,” write the researchers, led by Paul Siu Fai Yip, PhD, of the HKJC Center for Suicide Research and Prevention, University of Hong Kong, China.
The findings were published online Aug. 16 in Injury Prevention.
Global public health concern
Around the world, approximately 800,000 individuals die by suicide each year, while many others attempt suicide. Yet suicide has not received the same level of attention as other global public health concerns, such as HIV/AIDS and cancer, the investigators write.
They examined data from the Global Burden of Disease Study 2019 to assess how demographic and epidemiologic factors contributed to the number of suicide deaths during the past 30 years.
The researchers also analyzed relationships between population growth, population age structure, income level, and gender- and age-specific suicide rates.
The Global Burden of Disease Study 2019 includes information from 204 countries about 369 diseases and injuries by age and gender. The dataset also includes population estimates for each year by location, age group, and gender.
In their analysis, the investigators looked at changes in suicide rates and the number of suicide deaths from 1990 to 2019 by gender and age group in the four income level regions defined by the World Bank. These categories include low-income, lower-middle–income, upper-middle–income, and high-income regions.
Number of deaths versus suicide rates
The number of deaths was 738,799 in 1990 and 758,696 in 2019.
The largest increase in deaths occurred in the lower-middle–income region, where the number of suicide deaths increased by 72,550 (from 232,340 to 304,890).
Population growth (300,942; 1,512.5%) was the major contributor to the overall increase in total number of suicide deaths. The second largest contributor was population age structure (189,512; 952.4%).
However, the effects of these factors were offset to a large extent by the effect of reduction in overall suicide rates (−470,556; −2,364.9%).
Interestingly, the overall suicide rate per 100,000 population decreased from 13.8 in 1990 to 9.8 in 2019.
The upper-middle–income region had the largest decline (−6.25 per 100,000), and the high-income region had the smallest decline (−1.77 per 100,000). Suicide rates also decreased in lower-middle–income (−2.51 per 100,000) and low-income regions (−1.96 per 100,000).
Reasons for the declines across all regions “have yet to be determined,” write the investigators. International efforts coordinated by the United Nations and World Health Organization likely contributed to these declines, they add.
‘Imbalance of resources’
The overall reduction in suicide rate of −4.01 per 100,000 “was mainly due” to reduction in age-specific suicide rates (−6.09; 152%), the researchers report.
This effect was partly offset, however, by the effect of the changing population age structure (2.08; −52%). In the high-income–level region, for example, the reduction in age-specific suicide rate (−3.83; 216.3%) was greater than the increase resulting from the change in population age structure (2.06; −116.3%).
“The overall contribution of population age structure mainly came from the 45-64 (565.2%) and 65+ (528.7%) age groups,” the investigators write. “This effect was observed in middle-income– as well as high-income–level regions, reflecting the global effect of population aging.”
They add that world populations will “experience pronounced and historically unprecedented aging in the coming decades” because of increasing life expectancy and declining fertility.
Men, but not women, had a notable increase in total number of suicide deaths. The significant effect of male population growth (177,128; 890.2% vs. 123,814; 622.3% for women) and male population age structure (120,186; 604.0% vs. 69,325; 348.4%) were the main factors that explained this increase, the investigators note.
However, from 1990 to 2019, the overall suicide rate per 100,000 men decreased from 16.6 to 13.5 (–3.09). The decline in overall suicide rate was even greater for women, from 11.0 to 6.1 (–4.91).
This finding was particularly notable in the upper-middle–income region (–8.12 women vs. –4.37 men per 100,000).
“This study highlighted the considerable imbalance of the resources in carrying out suicide prevention work, especially in low-income and middle-income countries,” the investigators write.
“It is time to revisit this situation to ensure that sufficient resources can be redeployed globally to meet the future challenges,” they add.
The study was funded by a Humanities and Social Sciences Prestigious Fellowship, which Dr. Yip received. He declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The overall global number of deaths by suicide increased by almost 20,000 during the past 30 years, new research shows.
The increase occurred despite a significant decrease in age-specific suicide rates from 1990 through 2019, according to data from the Global Burden of Disease Study 2019.
Population growth, population aging, and changes in population age structure may explain the increase in number of suicide deaths, the investigators note.
“As suicide rates are highest among the elderly (70 years or above) for both genders in almost all regions of the world, the rapidly aging population globally will pose huge challenges for the reduction in the number of suicide deaths in the future,” write the researchers, led by Paul Siu Fai Yip, PhD, of the HKJC Center for Suicide Research and Prevention, University of Hong Kong, China.
The findings were published online Aug. 16 in Injury Prevention.
Global public health concern
Around the world, approximately 800,000 individuals die by suicide each year, while many others attempt suicide. Yet suicide has not received the same level of attention as other global public health concerns, such as HIV/AIDS and cancer, the investigators write.
They examined data from the Global Burden of Disease Study 2019 to assess how demographic and epidemiologic factors contributed to the number of suicide deaths during the past 30 years.
The researchers also analyzed relationships between population growth, population age structure, income level, and gender- and age-specific suicide rates.
The Global Burden of Disease Study 2019 includes information from 204 countries about 369 diseases and injuries by age and gender. The dataset also includes population estimates for each year by location, age group, and gender.
In their analysis, the investigators looked at changes in suicide rates and the number of suicide deaths from 1990 to 2019 by gender and age group in the four income level regions defined by the World Bank. These categories include low-income, lower-middle–income, upper-middle–income, and high-income regions.
Number of deaths versus suicide rates
The number of deaths was 738,799 in 1990 and 758,696 in 2019.
The largest increase in deaths occurred in the lower-middle–income region, where the number of suicide deaths increased by 72,550 (from 232,340 to 304,890).
Population growth (300,942; 1,512.5%) was the major contributor to the overall increase in total number of suicide deaths. The second largest contributor was population age structure (189,512; 952.4%).
However, the effects of these factors were offset to a large extent by the effect of reduction in overall suicide rates (−470,556; −2,364.9%).
Interestingly, the overall suicide rate per 100,000 population decreased from 13.8 in 1990 to 9.8 in 2019.
The upper-middle–income region had the largest decline (−6.25 per 100,000), and the high-income region had the smallest decline (−1.77 per 100,000). Suicide rates also decreased in lower-middle–income (−2.51 per 100,000) and low-income regions (−1.96 per 100,000).
Reasons for the declines across all regions “have yet to be determined,” write the investigators. International efforts coordinated by the United Nations and World Health Organization likely contributed to these declines, they add.
‘Imbalance of resources’
The overall reduction in suicide rate of −4.01 per 100,000 “was mainly due” to reduction in age-specific suicide rates (−6.09; 152%), the researchers report.
This effect was partly offset, however, by the effect of the changing population age structure (2.08; −52%). In the high-income–level region, for example, the reduction in age-specific suicide rate (−3.83; 216.3%) was greater than the increase resulting from the change in population age structure (2.06; −116.3%).
“The overall contribution of population age structure mainly came from the 45-64 (565.2%) and 65+ (528.7%) age groups,” the investigators write. “This effect was observed in middle-income– as well as high-income–level regions, reflecting the global effect of population aging.”
They add that world populations will “experience pronounced and historically unprecedented aging in the coming decades” because of increasing life expectancy and declining fertility.
Men, but not women, had a notable increase in total number of suicide deaths. The significant effect of male population growth (177,128; 890.2% vs. 123,814; 622.3% for women) and male population age structure (120,186; 604.0% vs. 69,325; 348.4%) were the main factors that explained this increase, the investigators note.
However, from 1990 to 2019, the overall suicide rate per 100,000 men decreased from 16.6 to 13.5 (–3.09). The decline in overall suicide rate was even greater for women, from 11.0 to 6.1 (–4.91).
This finding was particularly notable in the upper-middle–income region (–8.12 women vs. –4.37 men per 100,000).
“This study highlighted the considerable imbalance of the resources in carrying out suicide prevention work, especially in low-income and middle-income countries,” the investigators write.
“It is time to revisit this situation to ensure that sufficient resources can be redeployed globally to meet the future challenges,” they add.
The study was funded by a Humanities and Social Sciences Prestigious Fellowship, which Dr. Yip received. He declared no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MRI is a poor disability predictor in secondary progressive MS
, new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.
The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.
However, “it is unclear if these associations are clinically meaningful,” they added.
Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.
The findings were published online July 26 in the Multiple Sclerosis Journal.
ASCEND data analysis
Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.
However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.
In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.
Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.
The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
Few significant associations
The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.
Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.
For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.
Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.
Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.
After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
Important disability contributors missed
The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).
Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).
Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.
From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.
“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.
The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.
“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
‘Interesting and provocative’
Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”
“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.
The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.
Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.
She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.
“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.
“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.
These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.
The investigators and Dr. Yeh have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.
The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.
However, “it is unclear if these associations are clinically meaningful,” they added.
Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.
The findings were published online July 26 in the Multiple Sclerosis Journal.
ASCEND data analysis
Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.
However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.
In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.
Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.
The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
Few significant associations
The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.
Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.
For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.
Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.
Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.
After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
Important disability contributors missed
The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).
Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).
Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.
From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.
“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.
The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.
“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
‘Interesting and provocative’
Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”
“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.
The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.
Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.
She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.
“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.
“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.
These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.
The investigators and Dr. Yeh have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests. Analysis from the phase 3 ASCEND trial of nearly 900 patients showed that MRI measures were not associated with worsening of scores on the Expanded Disability Status Scale (EDSS), the most widely used physical outcome measure.
The few associations that were shown between MRI measures and clinical outcomes “were with the newer and possibly more sensitive outcomes” – the Timed 25-Foot Walk (T25FW) and Nine-Hole Peg Test (NHPT), wrote the investigators, led by Marcus W. Koch, MD, PhD, associate professor of neurology in the MS program at the University of Calgary, Canada.
However, “it is unclear if these associations are clinically meaningful,” they added.
Worsening on the NHPT at 48 weeks was associated with a 0.86% loss in normalized brain volume; worsening at 96 weeks was associated with a 1.47% loss.
The findings were published online July 26 in the Multiple Sclerosis Journal.
ASCEND data analysis
Although brain volume loss occurs in all forms of MS, it is believed to be particularly relevant in SPMS. Clinical trials often use MRI measures of brain volume as endpoints, likely on the assumption that these measures indicate worsening disability.
However, brain volume loss proceeds slowly. Changes that occur during the typical 2-year study period may not be associated with significant physical or cognitive disability.
In the current study, investigators examined data from the ASCEND trial, which assessed the use of natalizumab for patients with SPMS, to examine these potential associations. Eligible participants in ASCEND were between ages 18 and 58 years, had had SPMS for 2 or more years, had had disability progression during the previous year, and had an EDSS score between 3.0 and 6.5 at baseline.
Participants underwent gadolinium-enhanced cranial MRI at screening and at 24, 48, 72, and 96 weeks. MRI outcomes included normalized brain volume, normalized cortical gray matter volume, and normalized whole gray matter volume. The ASCEND investigators also examined the number and volume of T2 and contrast-enhancing lesions.
The study’s clinical outcomes included scores on the EDSS, T25FW, and NHPT, which were administered at baseline and every 12 weeks thereafter. Participants also underwent the Symbol Digit Modalities Test (SDMT), which is a cognitive assessment, at baseline and every 4 weeks thereafter. In addition, 3-month confirmed disability progression was measured every 12 weeks.
Few significant associations
The investigators’ analysis included 889 patients (61.9% women; median age, 48 years). The median EDSS score at screening was 6.
Brain volume measures decreased consistently during follow-up. Mean volume loss at 96 weeks was about 1%. In contrast, T2 lesion volume changed little during follow-up. The cumulative number of contrast-enhancing lesions and the cumulative number of new or newly enlarging T2 lesions increased steadily during follow-up.
For an increasing number of participants, scores on the EDSS, NHPT, and T25FW worsened significantly during follow-up. Performance on SDMT, however, changed little. Of all the clinical measures, the NHPT was most consistently associated with MRI measures.
Among patients whose NHPT score worsened at 48 weeks, there was greater loss of normalized brain volume (0.86%, P = .02), normalized cortical gray matter volume (1.15%, P = .03), and normalized whole gray matter volume (1.08%, P = .03) than among those whose NHPT score did not worsen.
Among patients whose NHPT score worsened at 96 weeks, there was greater normalized brain volume loss (1.47%, P = .002), greater increase in T2 lesion volume (4.68%, P = .02), and a greater number of cumulative new or newly enlarging T2 lesions (7.81, P = .03) than those whose NHPT score did not worsen.
After adjusting the data for covariables, the investigators found few significant associations between MRI measures and clinical outcomes. Worsening on the EDSS and SDMT was not associated with any MRI outcome.
Important disability contributors missed
The odds ratio of 3-month confirmed worsening on the T25FW at 96 weeks was 2.25 for patients with more than 10 cumulative new or newly enlarging T2 lesions (P = .03). The OR of 3-month confirmed worsening on the NHPT at 96 weeks was 3.04 for patients with more than 10 such lesions (P = .03).
Greater normalized brain volume loss at 48 weeks was associated with a greater risk for worsening disability on the NHPT at 48 and 96 weeks. For patients with a volume loss greater than 1.5%, the OR of worsening NHPT at 96 weeks was 4.69 (P = .05).
Although previous cross-sectional studies have shown correlations between brain volume and cognitive dysfunction, the current investigators found no association between change in SDMT performance and MRI measures.
From the ASCEND dataset, they found that performance on the SDMT unexpectedly improved with time, perhaps because of a practice effect.
“The SDMT may therefore not adequately reflect the steady cognitive decline that people with SPMS experience,” the investigators wrote.
The lack of association between MRI measures and clinical outcomes may indicate that traditional MRI does not measure important contributors to disability, they noted.
“Although the investigated volume measures in this study are currently the most commonly used in clinical trials, newer MRI metrics such as thalamic or corpus callosum atrophy may have a closer relation to clinical outcome,” they added.
‘Interesting and provocative’
Commenting on the findings, E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children, Toronto, called the study “interesting and provocative.”
“Other studies previously have shown associations between disability and progression, but many have been cross-sectional,” said Dr. Yeh, who was not involved with the research.
The current study is longitudinal and analyzes carefully documented follow-up data from a clinical trial, she noted. However, the 2-year follow-up period was short, considering the pace at which whole brain volume change occurs, Dr. Yeh said.
Some patients with MS have greater brain volume loss than others. Because of this variability, researchers often examine a population’s average brain volume loss. “When you look at averages, it makes it more difficult to understand if the larger brain volume losses are actually associated with change,” said Dr. Yeh.
She noted that because the study population had high EDSS scores at baseline, it is not surprising that the NHPT and the T25FW were more strongly associated with change in brain volume than the EDSS was. Large changes in EDSS score probably did not occur during follow-up, she added.
“We’ll continue to use the EDSS, because it’s what we have,” said Dr. Yeh. However, newer measures, such as the NHPT and the T25FW, may provide better information, she said. Similarly, composite measures of cognition, such as the Brief International Cognitive Assessment for MS, may be superior to the SDMT but take longer to administer.
“We need to look more deeply at which MRI measures are the best for predicting outcome and that correlate well in a short period of time,” said Dr. Yeh.
These measures could include specific regional brain volumes “and more advanced measures that look at axonal injury or axonal loss.” Studies with longer follow-up are also necessary, she concluded.
The investigators and Dr. Yeh have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From Multiple Sclerosis Journal
Progressive disability in MS explained?
Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).
“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.
The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.
The findings were published online July 14 in Neurology.
Lesion evolution
MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.
Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.
Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.
They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.
Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.
Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.
An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.
Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.
In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.
Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.
Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
Complete resolution
Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).
Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).
Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.
For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.
Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm2) than in those with NMOSD (104 mm2; P = .02) or MS (36 mm2; P < .001).
Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm2) and NMOSD (309 mm2) groups; both experienced greater reductions than the MS group (23 mm2; P < .001).
Lesion prevention
Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.
Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.
“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.
He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.
“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
Differences in pathology
Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.
“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.
The study’s cross-sectional comparison was its main strength, he noted.
“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”
The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.
Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.
“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”
The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.
Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.
The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.
This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).
“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.
The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.
The findings were published online July 14 in Neurology.
Lesion evolution
MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.
Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.
Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.
They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.
Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.
Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.
An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.
Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.
In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.
Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.
Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
Complete resolution
Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).
Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).
Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.
For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.
Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm2) than in those with NMOSD (104 mm2; P = .02) or MS (36 mm2; P < .001).
Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm2) and NMOSD (309 mm2) groups; both experienced greater reductions than the MS group (23 mm2; P < .001).
Lesion prevention
Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.
Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.
“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.
He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.
“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
Differences in pathology
Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.
“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.
The study’s cross-sectional comparison was its main strength, he noted.
“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”
The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.
Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.
“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”
The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.
Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.
The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.
This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from a retrospective study show that complete resolution of brain lesions on MRI was more common among patients with myelin-oligodendrocyte-glycoprotein-IgG-associated disorder (MOGAD). Complete resolution occurred in 72% of the group with MOGAD, versus 17% of those with MS and 14% of those with aquaporin-4-positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD).
“What we found was, with MOGAD in particular, many of the lesions resolved completely,” said co-investigator Eoin Flanagan, MBBCh, neurologist, Mayo Clinic, Rochester, Minn. “That fits with MOGAD having a fairly good prognosis and patients not developing much long-term disability with that disease,” he said.
The researchers also studied whether scarring may account for the absence of slowly progressive disability among patients with AQP4+ NMOSD and MOGAD compared with patients with MS. “The differences in scarring that we found will help physicians distinguish these three diseases more easily to aid in diagnosis. More importantly, our findings improve our understanding of the mechanisms of nerve damage in these three diseases and may suggest an important role of such scars in the development of long-term disability in MS,” Dr. Flanagan said in a statement.
The findings were published online July 14 in Neurology.
Lesion evolution
MOGAD, AQP4+ NMOSD, and MS are inflammatory demyelinating disorders that share certain manifestations. However, these disorders differ in important ways, including the severity of attacks and their clinical course.
Although patients with MOGAD and AQP4+ NMOSD generally have severe attacks that bring major disability, the clinical course of these disorders is better than initial attacks would suggest. In contrast, patients with MS have comparatively mild attacks that are associated with a high risk for progressive disability.
Previous studies of these demyelinating disorders have examined the shape and location of lesions but not change over time. Observing these lesions’ development and resolution could provide information about disease course and influence treatment and the monitoring of disease activity, the current researchers noted.
They retrospectively identified consecutive patients with MOGAD, AQP4+ NMOSD, or MS who presented to the Mayo Clinic between January 2000 and August 2019. Data from a cohort of patients with MS in Olmsted County, Minn., were also included.
Eligible participants had experienced a first brain or myelitis attack, had undergone MRI of the brain or spinal cord within 6 weeks of the attack nadir, and had undergone a follow-up MRI 6 months after the attack.
Patients who experienced a relapse during follow-up in the same region as the initial attack were excluded. Concomitant brain and myelitis attacks were analyzed separately.
An index lesion was identified for each patient. The index lesion was defined as an acute lesion that provided an anatomic explanation for the clinical symptoms. If multiple lesions were present, the largest of them was chosen as the index lesion. MRIs were examined by neuroradiologists who were blinded to patients’ diagnoses and serology results.
Among the 156 participants, 67 had MS (76% women), 51 had AQP4+ NMOSD (80% women), and 38 had MOGAD (45% women). The median age at first attack for the groups was 37, 53, and 25 years, respectively.
In addition, 63 patients had relapsing-remitting MS, two had a single attack of progressive MS, and two had clinically isolated syndrome. No patients with NMOSD or MOGAD had developed progressive disease at final follow-up.
Participants experienced a total of 81 brain attacks and 91 myelitis attacks. Sixteen patients had experienced both a brain attack and a myelitis attack.
Symptoms corresponding to the index brain lesions were brainstem or cerebellar syndrome (56), encephalopathy or focal symptoms (12), or combinations of these (13). Among patients with an index myelitis attack, 31 had cervical involvement, 21 had thoracic involvement, and 39 had involvement of both regions.
Complete resolution
Results showed that 72% of patients with MOGAD experienced complete resolution of the brain index lesion, compared with 17% of patients with MS and 14% of patients with NMOSD (P < .001).
Similarly, 79% of the MOGAD group experienced complete resolution of the myelitis index lesion, compared with no members of the MS or NMOSD groups (P < .001 for both comparisons).
Complete resolution of all T2-abnormalities at MRI follow-up was more common in the MOGAD group than in the other two groups.
For brain attacks, complete resolution occurred in 39% of patients with MOGAD, 10% of patients with NMOSD, and 5% of patients with MS. For spinal cord attacks, complete resolution occurred in 79% of patients with MOGAD, versus none of the patients with NMOSD or MS.
Median reduction in T2 lesion area on follow-up axial brain MRI was larger in patients with MOGAD (213 mm2) than in those with NMOSD (104 mm2; P = .02) or MS (36 mm2; P < .001).
Reductions in lesion size on sagittal spine MRI follow-up were similar between the MOGAD (262 mm2) and NMOSD (309 mm2) groups; both experienced greater reductions than the MS group (23 mm2; P < .001).
Lesion prevention
Dr. Flanagan noted that the diagnosis of MOGAD is based on a test for MOG antibody, but sometimes false positive results occur. “A single follow-up MRI can be useful, showing that if all the lesions went away, you would be more confident that it would be MOGAD,” he said.
Study participants with MS experienced less lesion healing than the patients with MOGAD or NMOSD.
“We now have very effective medications in MS to prevent new lesions from occurring,” Dr. Flanagan said. The study highlights the importance of lesion prevention, “because when you do get a lesion, it does tend to stay and not recover completely,” he added.
He noted that the resolution of lesions in the study population may reflect remyelination. Future research examining whether remyelination is more efficient in MOGAD than in the other disorders could possibly lead to new approaches for MS treatment, said Dr. Flanagan.
“Maybe some of the MOGAD lesions are from edema. When we use steroids, that tends to resolve and not leave a scar. So, that’s another possibility. We’d like to better understand that,” he said.
Differences in pathology
Commenting on the findings, Bruce Cree, MD, PhD, professor of neurology, Weill Institute for Neurosciences, University of California, San Francisco, noted that the study is one of the first to systematically examine and compare MRI lesion evolution across three disease states.
“What they put their finger on are differences in the fundamental pathology of these three different diseases,” said Dr. Cree, who was not involved with the research.
The study’s cross-sectional comparison was its main strength, he noted.
“The main weakness, from my point of view, is that in these three disorders, optic nerve involvement is very common,” Dr. Cree said. “In this paper, no analysis of optic nerve lesions by MRI was performed.”
The researchers acknowledge this limitation and explain that they did not have consistent, dedicated orbital imaging for such an analysis.
Dr. Cree noted that the findings also provide a reminder that the pathogenesis of MOGAD is not yet clear.
“We know that these anti-MOG antibodies are associated with this demyelinating disorder, but whether these antibodies have a pathogenic role has yet to be clearly demonstrated,” said Dr. Cree. “What is actually going on within these lesions [is also] not fully understood.”
The finding that MOGAD lesions can resolve completely suggests that repair mechanisms are at work within the brain and spinal cord, he noted.
Being able to understand and comprehend what those mechanisms at work are and why they occur in MOGAD but not in NMOSD or MS “would be of enormous clinical advantage,” he said.
The current study also highlights the importance of incorporating imaging into clinical trials that study these rare disorders, especially serial imaging for MOGAD, Dr. Cree added.
This imaging is vital not only for developing new treatments but also for understanding the clinical impact of a given medication. “We really need rigorous imaging to be applied to these rare disorders, just as was done with MS,” Dr. Cree concluded.
The study was funded by the National Institute of Neurological Disorders and Stroke. Dr. Flanagan has received research support from MedImmune/Viela Bio. Dr. Cree is working with two of the researchers on the steering committee for the N-MOmentum trial of inebilizumab in patients with NMOSD. He has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From Neurology
Atogepant reduces migraine days: ADVANCE trial results published
full results from a phase 3 trial suggest.
AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.
The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.
The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.
“Overall, this study showed us that atogepant was safe and surprisingly seems to be pretty effective regardless of the dose,” said lead author Jessica Ailani, MD, director of MedStar Georgetown Headache Center and associate professor of neurology at Georgetown University, Washington.
All doses effective
The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.
After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.
The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).
Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).
In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).
The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
Multidose flexibility
“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.
The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.
“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.
Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”
An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.
“You can easily identify patients who would do well on this medication,” she added.
In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
“Well-conducted study”
Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.
The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.
The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.
It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”
In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”
Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.
The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
full results from a phase 3 trial suggest.
AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.
The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.
The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.
“Overall, this study showed us that atogepant was safe and surprisingly seems to be pretty effective regardless of the dose,” said lead author Jessica Ailani, MD, director of MedStar Georgetown Headache Center and associate professor of neurology at Georgetown University, Washington.
All doses effective
The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.
After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.
The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).
Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).
In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).
The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
Multidose flexibility
“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.
The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.
“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.
Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”
An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.
“You can easily identify patients who would do well on this medication,” she added.
In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
“Well-conducted study”
Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.
The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.
The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.
It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”
In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”
Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.
The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
full results from a phase 3 trial suggest.
AbbVie, the company developing the oral therapy, announced topline results of the ADVANCE trial of atogepant last year. Safety results were presented in April at the 2021 annual meeting of the American Academy of Neurology.
The full results were published online Aug. 19 in the New England Journal of Medicine ahead of the upcoming target action date of the U.S. Food and Drug Administration.
The multicenter study included nearly 900 patients who were randomly assigned to receive either placebo or one of three doses of atogepant for 12 weeks. The mean number of monthly migraine days decreased by about 4 for all three doses of the active treatment, compared with a reduction of 2.5 days with placebo.
“Overall, this study showed us that atogepant was safe and surprisingly seems to be pretty effective regardless of the dose,” said lead author Jessica Ailani, MD, director of MedStar Georgetown Headache Center and associate professor of neurology at Georgetown University, Washington.
All doses effective
The study included 873 patients with episodic migraine with or without aura. Patients who were not assigned to the placebo control group received either 10 mg, 30 mg, or 60 mg of atogepant once daily.
After a 4-week screening period, all patients received treatment for 12 weeks and then entered a 4-week safety follow-up period. In total, the participants completed eight scheduled clinical visits.
The mean reduction from baseline in the mean number of migraine days per month was 3.7 with the 10-mg dose of atogepant, 3.9 with the 30-mg dose, 4.2 with the 60-mg dose, and 2.5 with placebo. The differences between each active dose and placebo was statistically significant (P < .001).
Treatment with the CGRP inhibitor was also associated with a reduction in the mean number of headache days per month. The mean reduction from baseline was 3.9 days for the 10-mg dose, 4.0 days for the 30-mg dose, 4.2 days for the 60-mg dose, and 2.5 days for placebo (P < .001 for all comparisons with placebo).
In addition, for 55.6% of the 10-mg group, 58.7% of the 30-mg group, 60.8% of the 60-mg group, and 29.0% of the control group, there was a reduction of at least 50% in the 3-month average number of migraine days per month (P < .001 for each vs. placebo).
The most commonly reported adverse events (AEs) among patients who received atogepant were constipation (6.9%-7.7% across doses), nausea (4.4%-6.1%), and upper respiratory tract infection (1.4%-3.9%). Frequency of AEs did not differ between the active-treatment groups and the control group, and no relationships between AEs and atogepant dose were observed.
Multidose flexibility
“Side effects were pretty even across the board,” said Dr. Ailani. She noted that the reported AEs were expected because of atogepant’s mechanism of action. In addition, the rate of discontinuation in the study was low.
The proportion of participants who experienced a reduction in monthly migraine days of at least 50% grew as time passed. “By the end of this study, your chance of having a greater than 50% response is about 75%,” Dr. Ailani said.
“Imagine telling your patient, ‘You stick on this drug for 3 months, and I can almost guarantee you that you’re going to get better,’” she added.
Although the treatment has no drug-drug contraindications, drug-drug interactions may occur. “The availability of various doses would allow clinicians to adjust treatment to avoid potential drug-drug interactions,” said Dr. Ailani. “That multidose flexibility is very important.”
An FDA decision on atogepant could be made in the coming months. “I’m hopeful, as a clinician, that it is positive news, because we really have waited a long time for something like this,” Dr. Ailani said.
“You can easily identify patients who would do well on this medication,” she added.
In a different study of atogepant among patients with chronic migraine, there were recruitment delays because of the pandemic. That study is now almost complete, Dr. Ailani reported.
“Well-conducted study”
Commenting on the findings, Kathleen B. Digre, MD, chief of the division of headache and neuro-ophthalmology at the University of Utah Health, Salt Lake City, expressed enthusiasm for the experimental drug. “I’m excited to see another treatment modality for migraine,” said Dr. Digre, who was not involved with the research. “It was a very well-conducted study,” she added.
The treatment arms were almost identical in regard to disease severity, and all the doses showed an effect. Although the difference in reduction of monthly migraine days in comparison with placebo was numerically small, “for people who have frequent migraine, it’s important,” Dr. Digre said.
The results for atogepant should be viewed in a larger context, however. “Even though it’s a treatment that works better than placebo for well-matched controls, it may not be a medication that everybody’s going to respond to,” she noted. “And we can’t generalize it for some of the most disabled people, which is for chronic migraine,” she said.
It is significant that the study was published in the New England Journal of Medicine, Dr. Digre noted. “Sometimes migraine is dismissed as not important and not affecting people’s lives,” she said. “That makes me very happy to see migraine being taken seriously by our major journals.”
In addition, she noted that the prospects for FDA approval of atogepant seem favorable. “I’m hopeful that they will approve it, because it’s got a low side-effect profile, plus it’s effective.”
Migraine-specific preventive therapy has emerged only in the past few years. “I’m so excited to see this surge of preventive medicine for migraine,” Dr. Digre said. “It’s so important, because we see so many people who are disabled by migraine,” she added.
The study was funded by Allergan before atogepant was acquired by AbbVie. Dr. Ailani has received honoraria from AbbVie for consulting, has received compensation from Allergan and AbbVie for participating in a speakers’ bureau, and has received clinical trial grants from Allergan. Dr. Digre has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Guidance on additional COVID-19 vaccine dose for MS patients
Patients aged 12 years and older with multiple sclerosis (MS) who are fully immunized against COVID-19 with either the Pfizer-BioNTech or Moderna mRNA vaccine may be eligible to receive an additional dose now, the National Multiple Sclerosis Society has announced.
New guidance, which is “based on available data from studies and expert consensus opinion” by a panel of MS neurologists and experts, was published Aug. 19 on the organization’s website.
The Food and Drug Administration has authorized an additional dose of the coronavirus vaccine for patients who are expected to not have a normal or adequate immune response to the first two doses. Patients with MS who use certain treatments have a reduced or absent antibody response to the vaccine, according to recent data.
“We want people living with MS to be aware of this additional dose and discuss when they need an additional dose or booster dose with their health care provider,” Julie Fiol, RN, MSW, associate vice president of health care access, National MS Society, said in an interview.
Those who may benefit from an additional dose include patients with MS who use sphingosine 1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, or alemtuzumab (Lemtrada), the National MS Society noted. These particular disease modifying therapies (DMTs) have a stronger effect on the immune system than do other treatments.
Protecting ‘the most vulnerable’
Sphingosine 1-phosphate receptor modulators include fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia), and ponesimod (Ponvory).
Anti-CD20 monoclonal antibodies include ocrelizumab (Ocrevus), ofatumumab (Kesimpta), rituximab (Rituxan), and corresponding biosimilars.
Current data do not support an additional dose for immunocompromised patients who received the Johnson & Johnson vaccine. The FDA and the Centers for Disease Control and Prevention are developing recommendations for these patients, and the National MS Society will update its guidance as needed, the organization noted in its statement.
“Like other medical decisions, the decision to get an additional dose is best made in partnership with your health care provider,” said Ms. Fiol. “Talk to your MS health care provider to determine what is best for you.”
MS itself does not compromise the immune system, but some MS therapies alter the immune system and reduce the body’s response to vaccination. Patients with MS who use B cell-depleting therapies have a better antibody response when they receive the vaccine 3 months or more after the last dose of MS therapy, according to the National MS Society.
Data suggest that patients with MS are not more susceptible to COVID-19 infection, severe illness, or death than are patients without MS. However, certain groups of patients with MS, such as those who receive B cell-depleting treatments, are more susceptible to having a severe case of COVID-19.
That said, “everyone will need a booster at some point. Those who take DMTs that have greater impact on the immune system are the most urgent need now,” the organization noted.
“Vaccination against COVID-19 is critical for public safety and, especially, the safety of the most vulnerable among us,” said Ms. Fiol. “We encourage everyone with MS get vaccinated.”
A version of this article first appeared on Medscape.com.
Patients aged 12 years and older with multiple sclerosis (MS) who are fully immunized against COVID-19 with either the Pfizer-BioNTech or Moderna mRNA vaccine may be eligible to receive an additional dose now, the National Multiple Sclerosis Society has announced.
New guidance, which is “based on available data from studies and expert consensus opinion” by a panel of MS neurologists and experts, was published Aug. 19 on the organization’s website.
The Food and Drug Administration has authorized an additional dose of the coronavirus vaccine for patients who are expected to not have a normal or adequate immune response to the first two doses. Patients with MS who use certain treatments have a reduced or absent antibody response to the vaccine, according to recent data.
“We want people living with MS to be aware of this additional dose and discuss when they need an additional dose or booster dose with their health care provider,” Julie Fiol, RN, MSW, associate vice president of health care access, National MS Society, said in an interview.
Those who may benefit from an additional dose include patients with MS who use sphingosine 1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, or alemtuzumab (Lemtrada), the National MS Society noted. These particular disease modifying therapies (DMTs) have a stronger effect on the immune system than do other treatments.
Protecting ‘the most vulnerable’
Sphingosine 1-phosphate receptor modulators include fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia), and ponesimod (Ponvory).
Anti-CD20 monoclonal antibodies include ocrelizumab (Ocrevus), ofatumumab (Kesimpta), rituximab (Rituxan), and corresponding biosimilars.
Current data do not support an additional dose for immunocompromised patients who received the Johnson & Johnson vaccine. The FDA and the Centers for Disease Control and Prevention are developing recommendations for these patients, and the National MS Society will update its guidance as needed, the organization noted in its statement.
“Like other medical decisions, the decision to get an additional dose is best made in partnership with your health care provider,” said Ms. Fiol. “Talk to your MS health care provider to determine what is best for you.”
MS itself does not compromise the immune system, but some MS therapies alter the immune system and reduce the body’s response to vaccination. Patients with MS who use B cell-depleting therapies have a better antibody response when they receive the vaccine 3 months or more after the last dose of MS therapy, according to the National MS Society.
Data suggest that patients with MS are not more susceptible to COVID-19 infection, severe illness, or death than are patients without MS. However, certain groups of patients with MS, such as those who receive B cell-depleting treatments, are more susceptible to having a severe case of COVID-19.
That said, “everyone will need a booster at some point. Those who take DMTs that have greater impact on the immune system are the most urgent need now,” the organization noted.
“Vaccination against COVID-19 is critical for public safety and, especially, the safety of the most vulnerable among us,” said Ms. Fiol. “We encourage everyone with MS get vaccinated.”
A version of this article first appeared on Medscape.com.
Patients aged 12 years and older with multiple sclerosis (MS) who are fully immunized against COVID-19 with either the Pfizer-BioNTech or Moderna mRNA vaccine may be eligible to receive an additional dose now, the National Multiple Sclerosis Society has announced.
New guidance, which is “based on available data from studies and expert consensus opinion” by a panel of MS neurologists and experts, was published Aug. 19 on the organization’s website.
The Food and Drug Administration has authorized an additional dose of the coronavirus vaccine for patients who are expected to not have a normal or adequate immune response to the first two doses. Patients with MS who use certain treatments have a reduced or absent antibody response to the vaccine, according to recent data.
“We want people living with MS to be aware of this additional dose and discuss when they need an additional dose or booster dose with their health care provider,” Julie Fiol, RN, MSW, associate vice president of health care access, National MS Society, said in an interview.
Those who may benefit from an additional dose include patients with MS who use sphingosine 1-phosphate receptor modulators, anti-CD20 monoclonal antibodies, or alemtuzumab (Lemtrada), the National MS Society noted. These particular disease modifying therapies (DMTs) have a stronger effect on the immune system than do other treatments.
Protecting ‘the most vulnerable’
Sphingosine 1-phosphate receptor modulators include fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia), and ponesimod (Ponvory).
Anti-CD20 monoclonal antibodies include ocrelizumab (Ocrevus), ofatumumab (Kesimpta), rituximab (Rituxan), and corresponding biosimilars.
Current data do not support an additional dose for immunocompromised patients who received the Johnson & Johnson vaccine. The FDA and the Centers for Disease Control and Prevention are developing recommendations for these patients, and the National MS Society will update its guidance as needed, the organization noted in its statement.
“Like other medical decisions, the decision to get an additional dose is best made in partnership with your health care provider,” said Ms. Fiol. “Talk to your MS health care provider to determine what is best for you.”
MS itself does not compromise the immune system, but some MS therapies alter the immune system and reduce the body’s response to vaccination. Patients with MS who use B cell-depleting therapies have a better antibody response when they receive the vaccine 3 months or more after the last dose of MS therapy, according to the National MS Society.
Data suggest that patients with MS are not more susceptible to COVID-19 infection, severe illness, or death than are patients without MS. However, certain groups of patients with MS, such as those who receive B cell-depleting treatments, are more susceptible to having a severe case of COVID-19.
That said, “everyone will need a booster at some point. Those who take DMTs that have greater impact on the immune system are the most urgent need now,” the organization noted.
“Vaccination against COVID-19 is critical for public safety and, especially, the safety of the most vulnerable among us,” said Ms. Fiol. “We encourage everyone with MS get vaccinated.”
A version of this article first appeared on Medscape.com.