Erik Greb

Lowering blood pressure for patients with intracerebral hemorrhage (ICH) does not improve functional recovery, a systematic review and meta-analysis shows, although it does reduce hematoma growth in these patients.

Despite the negative finding, the investigators observed broad variation in treatment effect among the studies they reviewed. They also found that target-based blood pressure treatment tended to improve function more than fixed-dose treatment.

“These data provide a strong message that early blood pressure–lowering treatment can control bleeding. This was not clear beforehand,” Craig Anderson, PhD, professor of neurology and epidemiology at the University of New South Wales, Sydney, said in an interview.

“But these data also indicate that the management of blood pressure in ICH is complex,” he added. Timing, type of drug, and type of patient must be considered, he said. “We need more data to allow better individualizing of such therapy.”

The results were presented at the European Stroke Organisation–World Stroke Organisation (ESO-WSO) Conference 2020.

Controversy about the efficacy of blood pressure reduction for patients with ICH continues, despite studies that have examined this question. In this analysis, Dr. Anderson and colleagues sought to examine the evidence from randomized controlled trials in this area and identify potentially overlooked heterogeneity among trials.

The investigators conducted a systematic review and meta-analysis of studies in the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE databases. They searched for randomized controlled trials of blood pressure management for adults with acute ICH, focusing on studies in which patients were enrolled within 7 days of ICH onset. These studies compared intensive blood pressure management with guideline-based management.

Investigators chose function, defined as Modified Rankin Scale (mRS) score at 90 days, as their primary outcome. Radiologic outcomes included absolute (>6 mL) and proportional (>33%) hematoma growth at 24 hours. They used the intention to treat dataset from each trial in their statistical analyses and created generalized linear mixed models with prespecified covariables using a one-stage approach.
 

Variation by drug

A total of 7,094 studies were identified, of which 50 were eligible for inclusion. Their analysis encompassed 16 studies for which the respective investigators were willing to share patient-level data. The analysis included data on 6,221 patients. The mean age of the patients was 64.2 years, 36.4% were women, and the median time from symptom onset to randomization was 3.8 hours.

Mean National Institutes of Health Stroke Scale score was approximately 11. Mean systolic blood pressure at baseline was 177 mm Hg, and mean hematoma volume was approximately 10.6 mL.

The difference in blood pressure between the intensive and guideline groups was approximately 8 mm Hg at 1 hour and 12 mm Hg at 24 hours.

Intensive blood pressure management did not affect function at 90 days. The adjusted odds ratio for unfavorable shift in mRS scores was 0.97 (95% CI, 0.88-1.06; P = .503). Intensive blood pressure management did, however, reduce hematoma growth (absolute aOR, 0.75; 95% CI, 0.60-0.92; P = .007; relative aOR, 0.82; 95% CI, 0.68-0.99; P = .034).

In prespecified subgroup analyses, they found a trend toward adverse outcomes among patients who received renin-angiotensin blockers and a trend toward benefit for patients who received alpha- or beta-receptor antagonists or calcium channel blockers. They did not observe a clear association between time of treatment and outcome.

In addition to hematoma growth, other factors influence prognosis after ICH, such as the patient’s status before ICH (for example, cardiovascular risk factors, age, and hypertensive effects on the brain, kidneys, and heart), the location of ICH and its effects on surrounding structures, and complications of care in hospitals, such as infection and bleeding, said Dr. Anderson.

They are conducting two ongoing clinical trials in patients with ICH. One, INTERACT3, is evaluating a “care bundle” quality control package that includes early intensive blood pressure lowering for patients with large ICH who undergo surgery.

The other, INTERACT4, is evaluating early blood pressure control in the ambulance for patients with suspected acute stroke. At least one-fifth of those patients will have ICH, said Dr. Anderson.
 

Prevention is essential

Among patients with ICH, much of the bleeding occurs before presentation at the hospital, Louis R. Caplan, MD, a neurologist at Beth Israel Deaconess Medical Center, Boston, said in an interview. Furthermore, the bleeding mainly occurs in the deep part of the brain where most of the important motor tracts are. “If those tracts are already hit, a little extra blood isn’t going to change things,” said Dr. Caplan, who was not involved in the research.

In addition, blood is pushed from inside the brain to the periphery until the pressure outside the brain is equal to the pressure inside it. “You can decrease the amount of bleeding significantly, but it probably doesn’t affect the outcome,” said Dr. Caplan.

One factor in patients’ apparent lack of functional improvement is that the mRS is not sensitive to minor changes in disability, he said. “You have to show a pretty important change for it to make a difference,” said Dr. Caplan.

In addition, recovery from a hemorrhage takes much longer than recovery from an infarct. Examining the population at 6 months would have been preferable to examining them at 90 days, but the investigators might not have 6-month data, said Dr. Caplan.

“The main thing is really prevention,” he concluded.

The study was conducted with funding from Takeda. Dr. Anderson reported receiving funding from the National Health and Medical Research Council of Australia and speaker fees from Takeda. Dr. Caplan has disclosed no relevant financial relationships.

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

Lowering blood pressure for patients with intracerebral hemorrhage (ICH) does not improve functional recovery, a systematic review and meta-analysis shows, although it does reduce hematoma growth in these patients.

Despite the negative finding, the investigators observed broad variation in treatment effect among the studies they reviewed. They also found that target-based blood pressure treatment tended to improve function more than fixed-dose treatment.

“These data provide a strong message that early blood pressure–lowering treatment can control bleeding. This was not clear beforehand,” Craig Anderson, PhD, professor of neurology and epidemiology at the University of New South Wales, Sydney, said in an interview.

“But these data also indicate that the management of blood pressure in ICH is complex,” he added. Timing, type of drug, and type of patient must be considered, he said. “We need more data to allow better individualizing of such therapy.”

The results were presented at the European Stroke Organisation–World Stroke Organisation (ESO-WSO) Conference 2020.

Controversy about the efficacy of blood pressure reduction for patients with ICH continues, despite studies that have examined this question. In this analysis, Dr. Anderson and colleagues sought to examine the evidence from randomized controlled trials in this area and identify potentially overlooked heterogeneity among trials.

The investigators conducted a systematic review and meta-analysis of studies in the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE databases. They searched for randomized controlled trials of blood pressure management for adults with acute ICH, focusing on studies in which patients were enrolled within 7 days of ICH onset. These studies compared intensive blood pressure management with guideline-based management.

Investigators chose function, defined as Modified Rankin Scale (mRS) score at 90 days, as their primary outcome. Radiologic outcomes included absolute (>6 mL) and proportional (>33%) hematoma growth at 24 hours. They used the intention to treat dataset from each trial in their statistical analyses and created generalized linear mixed models with prespecified covariables using a one-stage approach.
 

Variation by drug

A total of 7,094 studies were identified, of which 50 were eligible for inclusion. Their analysis encompassed 16 studies for which the respective investigators were willing to share patient-level data. The analysis included data on 6,221 patients. The mean age of the patients was 64.2 years, 36.4% were women, and the median time from symptom onset to randomization was 3.8 hours.

Mean National Institutes of Health Stroke Scale score was approximately 11. Mean systolic blood pressure at baseline was 177 mm Hg, and mean hematoma volume was approximately 10.6 mL.

The difference in blood pressure between the intensive and guideline groups was approximately 8 mm Hg at 1 hour and 12 mm Hg at 24 hours.

Intensive blood pressure management did not affect function at 90 days. The adjusted odds ratio for unfavorable shift in mRS scores was 0.97 (95% CI, 0.88-1.06; P = .503). Intensive blood pressure management did, however, reduce hematoma growth (absolute aOR, 0.75; 95% CI, 0.60-0.92; P = .007; relative aOR, 0.82; 95% CI, 0.68-0.99; P = .034).

In prespecified subgroup analyses, they found a trend toward adverse outcomes among patients who received renin-angiotensin blockers and a trend toward benefit for patients who received alpha- or beta-receptor antagonists or calcium channel blockers. They did not observe a clear association between time of treatment and outcome.

In addition to hematoma growth, other factors influence prognosis after ICH, such as the patient’s status before ICH (for example, cardiovascular risk factors, age, and hypertensive effects on the brain, kidneys, and heart), the location of ICH and its effects on surrounding structures, and complications of care in hospitals, such as infection and bleeding, said Dr. Anderson.

They are conducting two ongoing clinical trials in patients with ICH. One, INTERACT3, is evaluating a “care bundle” quality control package that includes early intensive blood pressure lowering for patients with large ICH who undergo surgery.

The other, INTERACT4, is evaluating early blood pressure control in the ambulance for patients with suspected acute stroke. At least one-fifth of those patients will have ICH, said Dr. Anderson.
 

Prevention is essential

Among patients with ICH, much of the bleeding occurs before presentation at the hospital, Louis R. Caplan, MD, a neurologist at Beth Israel Deaconess Medical Center, Boston, said in an interview. Furthermore, the bleeding mainly occurs in the deep part of the brain where most of the important motor tracts are. “If those tracts are already hit, a little extra blood isn’t going to change things,” said Dr. Caplan, who was not involved in the research.

In addition, blood is pushed from inside the brain to the periphery until the pressure outside the brain is equal to the pressure inside it. “You can decrease the amount of bleeding significantly, but it probably doesn’t affect the outcome,” said Dr. Caplan.

One factor in patients’ apparent lack of functional improvement is that the mRS is not sensitive to minor changes in disability, he said. “You have to show a pretty important change for it to make a difference,” said Dr. Caplan.

In addition, recovery from a hemorrhage takes much longer than recovery from an infarct. Examining the population at 6 months would have been preferable to examining them at 90 days, but the investigators might not have 6-month data, said Dr. Caplan.

“The main thing is really prevention,” he concluded.

The study was conducted with funding from Takeda. Dr. Anderson reported receiving funding from the National Health and Medical Research Council of Australia and speaker fees from Takeda. Dr. Caplan has disclosed no relevant financial relationships.

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

Lowering blood pressure for patients with intracerebral hemorrhage (ICH) does not improve functional recovery, a systematic review and meta-analysis shows, although it does reduce hematoma growth in these patients.

Despite the negative finding, the investigators observed broad variation in treatment effect among the studies they reviewed. They also found that target-based blood pressure treatment tended to improve function more than fixed-dose treatment.

“These data provide a strong message that early blood pressure–lowering treatment can control bleeding. This was not clear beforehand,” Craig Anderson, PhD, professor of neurology and epidemiology at the University of New South Wales, Sydney, said in an interview.

“But these data also indicate that the management of blood pressure in ICH is complex,” he added. Timing, type of drug, and type of patient must be considered, he said. “We need more data to allow better individualizing of such therapy.”

The results were presented at the European Stroke Organisation–World Stroke Organisation (ESO-WSO) Conference 2020.

Controversy about the efficacy of blood pressure reduction for patients with ICH continues, despite studies that have examined this question. In this analysis, Dr. Anderson and colleagues sought to examine the evidence from randomized controlled trials in this area and identify potentially overlooked heterogeneity among trials.

The investigators conducted a systematic review and meta-analysis of studies in the Cochrane Central Register of Controlled Trials, EMBASE, and MEDLINE databases. They searched for randomized controlled trials of blood pressure management for adults with acute ICH, focusing on studies in which patients were enrolled within 7 days of ICH onset. These studies compared intensive blood pressure management with guideline-based management.

Investigators chose function, defined as Modified Rankin Scale (mRS) score at 90 days, as their primary outcome. Radiologic outcomes included absolute (>6 mL) and proportional (>33%) hematoma growth at 24 hours. They used the intention to treat dataset from each trial in their statistical analyses and created generalized linear mixed models with prespecified covariables using a one-stage approach.
 

Variation by drug

A total of 7,094 studies were identified, of which 50 were eligible for inclusion. Their analysis encompassed 16 studies for which the respective investigators were willing to share patient-level data. The analysis included data on 6,221 patients. The mean age of the patients was 64.2 years, 36.4% were women, and the median time from symptom onset to randomization was 3.8 hours.

Mean National Institutes of Health Stroke Scale score was approximately 11. Mean systolic blood pressure at baseline was 177 mm Hg, and mean hematoma volume was approximately 10.6 mL.

The difference in blood pressure between the intensive and guideline groups was approximately 8 mm Hg at 1 hour and 12 mm Hg at 24 hours.

Intensive blood pressure management did not affect function at 90 days. The adjusted odds ratio for unfavorable shift in mRS scores was 0.97 (95% CI, 0.88-1.06; P = .503). Intensive blood pressure management did, however, reduce hematoma growth (absolute aOR, 0.75; 95% CI, 0.60-0.92; P = .007; relative aOR, 0.82; 95% CI, 0.68-0.99; P = .034).

In prespecified subgroup analyses, they found a trend toward adverse outcomes among patients who received renin-angiotensin blockers and a trend toward benefit for patients who received alpha- or beta-receptor antagonists or calcium channel blockers. They did not observe a clear association between time of treatment and outcome.

In addition to hematoma growth, other factors influence prognosis after ICH, such as the patient’s status before ICH (for example, cardiovascular risk factors, age, and hypertensive effects on the brain, kidneys, and heart), the location of ICH and its effects on surrounding structures, and complications of care in hospitals, such as infection and bleeding, said Dr. Anderson.

They are conducting two ongoing clinical trials in patients with ICH. One, INTERACT3, is evaluating a “care bundle” quality control package that includes early intensive blood pressure lowering for patients with large ICH who undergo surgery.

The other, INTERACT4, is evaluating early blood pressure control in the ambulance for patients with suspected acute stroke. At least one-fifth of those patients will have ICH, said Dr. Anderson.
 

Prevention is essential

Among patients with ICH, much of the bleeding occurs before presentation at the hospital, Louis R. Caplan, MD, a neurologist at Beth Israel Deaconess Medical Center, Boston, said in an interview. Furthermore, the bleeding mainly occurs in the deep part of the brain where most of the important motor tracts are. “If those tracts are already hit, a little extra blood isn’t going to change things,” said Dr. Caplan, who was not involved in the research.

In addition, blood is pushed from inside the brain to the periphery until the pressure outside the brain is equal to the pressure inside it. “You can decrease the amount of bleeding significantly, but it probably doesn’t affect the outcome,” said Dr. Caplan.

One factor in patients’ apparent lack of functional improvement is that the mRS is not sensitive to minor changes in disability, he said. “You have to show a pretty important change for it to make a difference,” said Dr. Caplan.

In addition, recovery from a hemorrhage takes much longer than recovery from an infarct. Examining the population at 6 months would have been preferable to examining them at 90 days, but the investigators might not have 6-month data, said Dr. Caplan.

“The main thing is really prevention,” he concluded.

The study was conducted with funding from Takeda. Dr. Anderson reported receiving funding from the National Health and Medical Research Council of Australia and speaker fees from Takeda. Dr. Caplan has disclosed no relevant financial relationships.

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

Concussion is associated with increased risk for subsequent development of attention-deficit/hyperactivity disorder (ADHD), as well as dementia and Parkinson’s disease, new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.

The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.

The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.

The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
 

Almost 190,000 participants

Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.

An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.

In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.

Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.

Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).

The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
 

Dose effect?

Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).

After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.

Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).

A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.

Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.

“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
 

Association versus causation

Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.

“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.

Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.

“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.

The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.

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

Concussion is associated with increased risk for subsequent development of attention-deficit/hyperactivity disorder (ADHD), as well as dementia and Parkinson’s disease, new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.

The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.

The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.

The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
 

Almost 190,000 participants

Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.

An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.

In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.

Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.

Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).

The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
 

Dose effect?

Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).

After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.

Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).

A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.

Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.

“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
 

Association versus causation

Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.

“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.

Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.

“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.

The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.

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

Concussion is associated with increased risk for subsequent development of attention-deficit/hyperactivity disorder (ADHD), as well as dementia and Parkinson’s disease, new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.

The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.

The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.

The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
 

Almost 190,000 participants

Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.

An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.

In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.

Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.

Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).

The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
 

Dose effect?

Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).

After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.

Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).

A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.

Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.

“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
 

Association versus causation

Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.

“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.

Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.

“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.

The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.

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

Late-onset epilepsy is linked to a substantial increased risk of subsequent dementia. Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy.

“This is an exciting area, as we are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other cohort studies are finding similar results, including the Veterans’ Health Study and the Framingham Study,” she added.

The study was published online Oct. 23 in Neurology
 

Bidirectional relationship?

Previous research has established that dementia is a risk factor for epilepsy, but recent studies also suggest an increased risk of incident dementia among patients with adult-onset epilepsy. Several risk factors for late-onset epilepsy, including diabetes and hypertension, also are risk factors for dementia. However, the effect of late-onset epilepsy on dementia risk in patients with these comorbidities has not been clarified.

To investigate, the researchers examined data from the Atherosclerosis Risk in Communities (ARIC) study. Participants include Black and White men and women from four U.S. communities. Baseline visits in this longitudinal cohort study began between 1987 and 1989, and follow-up included seven additional visits and regular phone calls.

The investigators identified participants with late-onset epilepsy by searching for Medicare claims related to seizures or epilepsy filed between 1991 and 2015. Those with two or more such claims and age of onset of 67 years or greater were considered to have late-onset epilepsy. Participants with preexisting conditions such as brain tumors or multiple sclerosis were excluded.

ARIC participants who presented in person for visits 2, 4, 5, and 6 underwent cognitive testing with the Delayed Word Recall Test, the Digit Symbol Substitution Test, and the Word Fluency Test.

Testing at visits 5 and 6 also included other tests, such as the Mini-Mental State Examination, the Boston Naming test, and the Wechsler Memory Scale-III. Dr. Johnson and colleagues excluded data for visit 7 from the analysis because dementia adjudication was not yet complete.

The researchers identified participants with dementia using data from visits 5 and 6 and ascertained time of dementia onset through participant and informant interviews, phone calls, and hospital discharge data. Participants also were screened for mild cognitive impairment (MCI) at visits 5 and 6.

Data were analyzed using a Cox proportional hazards model and multinomial logistic regression. In subsequent analyses, researchers adjusted the data for age, sex, race, smoking status, alcohol use, hypertension, diabetes, body mass index (BMI), APOE4 status, and prevalent stroke.

The researchers found that of 9,033 study participants, 671 had late-onset epilepsy. The late-onset epilepsy group was older at baseline (56.5 vs. 55.1 years) and more likely to have hypertension (38.9% vs. 33.3%), diabetes (16.1% vs. 9.6%), and two alleles of APOE4 genotype (3.9% vs. 2.5%), compared with those without the disorder.

In all, 1,687 participants developed dementia during follow-up. The rate of incident dementia was 41.6% in participants with late-onset epilepsy and 16.8% in participants without late-onset epilepsy. The adjusted hazard ratio of subsequent dementia in participants with late-onset epilepsy versus those without the disorder was 3.05 (95% confidence interval, 2.65-3.51).

The median time to dementia ascertainment after late-onset epilepsy was 3.66 years.
 

Counterintuitive finding

The relationship between late-onset epilepsy and subsequent dementia was stronger in patients without stroke. The investigators offered a possible explanation for this counterintuitive finding. “We observed an interaction between [late-onset epilepsy] and stroke, with a lower (but still substantial) association between [late-onset epilepsy] and dementia in those with a history of stroke. This may be due to the known strong association between stroke and dementia, which may wash out the contributions of [late-onset epilepsy] to cognitive impairment,” the researchers wrote.

“There may also be under-capturing of dementia diagnoses among participants with stroke in the ascertainment from [Centers for Medicare & Medicaid Services] codes, as physicians may be reluctant to make a separate code for ‘dementia’ in those with cognitive impairment after stroke,” they added.

When the researchers restricted the analysis only to participants who attended visits 5 and 6 and had late-onset epilepsy ascertainment available, they found that the relative risk ratio for dementia at visit 6 was 2.90 (95% CI, 1.22-6.92; P = .009). The RRR for MCI was 0.97 (95% CI, 0.39-2.38; P = .803). The greater functional impairment in patients with late-onset epilepsy may explain the lack of a relationship between late-onset epilepsy and MCI.

“It will be important for neurologists to be aware of the possibility of cognitive impairment following late-onset epilepsy and to check in with patients and family members to see if there are concerns,” said Dr. Johnson.

“We should also be talking about the importance of lowering other risk factors for dementia by making sure cardiovascular risk factors are controlled and encouraging physical and cognitive activity,” she added.

The results require confirmation in a clinical population, the investigators noted. In addition, future research is necessary to clarify whether seizures directly increase the risk of dementia or whether shared neuropathology between epilepsy and dementia explains the risk.

“In the near future, I plan to enroll participants with late-onset epilepsy in an observational study to better understand factors that may contribute to cognitive change. Collaborations will be key as we seek to further understand what causes these changes and what could be done to prevent them,” Dr. Johnson added.
 

Strengths and weaknesses

In an accompanying editorial, W. Allen Hauser, MD, professor emeritus of neurology and epidemiology at Columbia University in New York, and colleagues noted that the findings support a bidirectional relationship between dementia and epilepsy, adding that accumulation of amyloid beta peptide is a plausible underlying pathophysiology that may explain this relationship.

Future research should clarify the effect of factors such as seizure type, seizure frequency, and age of onset on the risk of dementia among patients with epilepsy, the editorialists wrote. Such investigations could help elucidate the underlying mechanisms of these conditions and help to improve treatment, they added.

Commenting on the findings, Ilo Leppik, MD, professor of neurology and pharmacy at the University of Minnesota in Minneapolis described the research as “a very well-done study by qualified researchers in the field. … For the last century, medicine has unfortunately become compartmentalized by specialty and then subspecialty. The brain and disorders of the brain do not recognize these silos. … It is not a stretch of the known science to begin to understand that epilepsy and dementia have common anatomical and physiological underpinnings.”

The long period of prospectively gathering data and the measurement of cognitive function through various modalities are among the study’s great strengths, said Dr. Leppik. However, the study’s weakness is its reliance on Medicare claims data, which mainly would reflect convulsive seizures.

“What is missing is how many persons had subtle focal-unaware seizures that may not be identified unless a careful history is taken,” said Dr. Leppik. “Thus, this study likely underestimates the frequency of epilepsy.”

Neurologists who evaluate a person with early dementia should be on the lookout for a history of subtle seizures, said Dr. Leppik. Animal studies suggest treatment with levetiracetam or brivaracetam may slow the course of dementia, and a clinical study in participants with early dementia is underway.

“Treatment with an antiseizure drug may prove to be beneficial, especially if evidence for the presence of subtle epilepsy can be found,” Dr. Leppik added.

Greater collaboration between epileptologists and dementia specialists and larger studies of antiseizure drugs are necessary, he noted. “These studies can incorporate sophisticated structural and biochemical [analyses] to better identify the relationships between brain mechanisms that likely underlie both seizures and dementia. The ultimate promise is that early treatment of seizures may alter the course of dementia,” Dr. Leppik said.

The study by Dr. Johnson and colleagues was supported by a contract from the National Institute on Aging; ARIC from the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the Department of Health & Human Services. The authors and Dr. Leppik have disclosed no relevant financial relationships.

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

Late-onset epilepsy is linked to a substantial increased risk of subsequent dementia. Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy.

“This is an exciting area, as we are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other cohort studies are finding similar results, including the Veterans’ Health Study and the Framingham Study,” she added.

The study was published online Oct. 23 in Neurology
 

Bidirectional relationship?

Previous research has established that dementia is a risk factor for epilepsy, but recent studies also suggest an increased risk of incident dementia among patients with adult-onset epilepsy. Several risk factors for late-onset epilepsy, including diabetes and hypertension, also are risk factors for dementia. However, the effect of late-onset epilepsy on dementia risk in patients with these comorbidities has not been clarified.

To investigate, the researchers examined data from the Atherosclerosis Risk in Communities (ARIC) study. Participants include Black and White men and women from four U.S. communities. Baseline visits in this longitudinal cohort study began between 1987 and 1989, and follow-up included seven additional visits and regular phone calls.

The investigators identified participants with late-onset epilepsy by searching for Medicare claims related to seizures or epilepsy filed between 1991 and 2015. Those with two or more such claims and age of onset of 67 years or greater were considered to have late-onset epilepsy. Participants with preexisting conditions such as brain tumors or multiple sclerosis were excluded.

ARIC participants who presented in person for visits 2, 4, 5, and 6 underwent cognitive testing with the Delayed Word Recall Test, the Digit Symbol Substitution Test, and the Word Fluency Test.

Testing at visits 5 and 6 also included other tests, such as the Mini-Mental State Examination, the Boston Naming test, and the Wechsler Memory Scale-III. Dr. Johnson and colleagues excluded data for visit 7 from the analysis because dementia adjudication was not yet complete.

The researchers identified participants with dementia using data from visits 5 and 6 and ascertained time of dementia onset through participant and informant interviews, phone calls, and hospital discharge data. Participants also were screened for mild cognitive impairment (MCI) at visits 5 and 6.

Data were analyzed using a Cox proportional hazards model and multinomial logistic regression. In subsequent analyses, researchers adjusted the data for age, sex, race, smoking status, alcohol use, hypertension, diabetes, body mass index (BMI), APOE4 status, and prevalent stroke.

The researchers found that of 9,033 study participants, 671 had late-onset epilepsy. The late-onset epilepsy group was older at baseline (56.5 vs. 55.1 years) and more likely to have hypertension (38.9% vs. 33.3%), diabetes (16.1% vs. 9.6%), and two alleles of APOE4 genotype (3.9% vs. 2.5%), compared with those without the disorder.

In all, 1,687 participants developed dementia during follow-up. The rate of incident dementia was 41.6% in participants with late-onset epilepsy and 16.8% in participants without late-onset epilepsy. The adjusted hazard ratio of subsequent dementia in participants with late-onset epilepsy versus those without the disorder was 3.05 (95% confidence interval, 2.65-3.51).

The median time to dementia ascertainment after late-onset epilepsy was 3.66 years.
 

Counterintuitive finding

The relationship between late-onset epilepsy and subsequent dementia was stronger in patients without stroke. The investigators offered a possible explanation for this counterintuitive finding. “We observed an interaction between [late-onset epilepsy] and stroke, with a lower (but still substantial) association between [late-onset epilepsy] and dementia in those with a history of stroke. This may be due to the known strong association between stroke and dementia, which may wash out the contributions of [late-onset epilepsy] to cognitive impairment,” the researchers wrote.

“There may also be under-capturing of dementia diagnoses among participants with stroke in the ascertainment from [Centers for Medicare & Medicaid Services] codes, as physicians may be reluctant to make a separate code for ‘dementia’ in those with cognitive impairment after stroke,” they added.

When the researchers restricted the analysis only to participants who attended visits 5 and 6 and had late-onset epilepsy ascertainment available, they found that the relative risk ratio for dementia at visit 6 was 2.90 (95% CI, 1.22-6.92; P = .009). The RRR for MCI was 0.97 (95% CI, 0.39-2.38; P = .803). The greater functional impairment in patients with late-onset epilepsy may explain the lack of a relationship between late-onset epilepsy and MCI.

“It will be important for neurologists to be aware of the possibility of cognitive impairment following late-onset epilepsy and to check in with patients and family members to see if there are concerns,” said Dr. Johnson.

“We should also be talking about the importance of lowering other risk factors for dementia by making sure cardiovascular risk factors are controlled and encouraging physical and cognitive activity,” she added.

The results require confirmation in a clinical population, the investigators noted. In addition, future research is necessary to clarify whether seizures directly increase the risk of dementia or whether shared neuropathology between epilepsy and dementia explains the risk.

“In the near future, I plan to enroll participants with late-onset epilepsy in an observational study to better understand factors that may contribute to cognitive change. Collaborations will be key as we seek to further understand what causes these changes and what could be done to prevent them,” Dr. Johnson added.
 

Strengths and weaknesses

In an accompanying editorial, W. Allen Hauser, MD, professor emeritus of neurology and epidemiology at Columbia University in New York, and colleagues noted that the findings support a bidirectional relationship between dementia and epilepsy, adding that accumulation of amyloid beta peptide is a plausible underlying pathophysiology that may explain this relationship.

Future research should clarify the effect of factors such as seizure type, seizure frequency, and age of onset on the risk of dementia among patients with epilepsy, the editorialists wrote. Such investigations could help elucidate the underlying mechanisms of these conditions and help to improve treatment, they added.

Commenting on the findings, Ilo Leppik, MD, professor of neurology and pharmacy at the University of Minnesota in Minneapolis described the research as “a very well-done study by qualified researchers in the field. … For the last century, medicine has unfortunately become compartmentalized by specialty and then subspecialty. The brain and disorders of the brain do not recognize these silos. … It is not a stretch of the known science to begin to understand that epilepsy and dementia have common anatomical and physiological underpinnings.”

The long period of prospectively gathering data and the measurement of cognitive function through various modalities are among the study’s great strengths, said Dr. Leppik. However, the study’s weakness is its reliance on Medicare claims data, which mainly would reflect convulsive seizures.

“What is missing is how many persons had subtle focal-unaware seizures that may not be identified unless a careful history is taken,” said Dr. Leppik. “Thus, this study likely underestimates the frequency of epilepsy.”

Neurologists who evaluate a person with early dementia should be on the lookout for a history of subtle seizures, said Dr. Leppik. Animal studies suggest treatment with levetiracetam or brivaracetam may slow the course of dementia, and a clinical study in participants with early dementia is underway.

“Treatment with an antiseizure drug may prove to be beneficial, especially if evidence for the presence of subtle epilepsy can be found,” Dr. Leppik added.

Greater collaboration between epileptologists and dementia specialists and larger studies of antiseizure drugs are necessary, he noted. “These studies can incorporate sophisticated structural and biochemical [analyses] to better identify the relationships between brain mechanisms that likely underlie both seizures and dementia. The ultimate promise is that early treatment of seizures may alter the course of dementia,” Dr. Leppik said.

The study by Dr. Johnson and colleagues was supported by a contract from the National Institute on Aging; ARIC from the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the Department of Health & Human Services. The authors and Dr. Leppik have disclosed no relevant financial relationships.

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

Late-onset epilepsy is linked to a substantial increased risk of subsequent dementia. Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy.

“This is an exciting area, as we are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other cohort studies are finding similar results, including the Veterans’ Health Study and the Framingham Study,” she added.

The study was published online Oct. 23 in Neurology
 

Bidirectional relationship?

Previous research has established that dementia is a risk factor for epilepsy, but recent studies also suggest an increased risk of incident dementia among patients with adult-onset epilepsy. Several risk factors for late-onset epilepsy, including diabetes and hypertension, also are risk factors for dementia. However, the effect of late-onset epilepsy on dementia risk in patients with these comorbidities has not been clarified.

To investigate, the researchers examined data from the Atherosclerosis Risk in Communities (ARIC) study. Participants include Black and White men and women from four U.S. communities. Baseline visits in this longitudinal cohort study began between 1987 and 1989, and follow-up included seven additional visits and regular phone calls.

The investigators identified participants with late-onset epilepsy by searching for Medicare claims related to seizures or epilepsy filed between 1991 and 2015. Those with two or more such claims and age of onset of 67 years or greater were considered to have late-onset epilepsy. Participants with preexisting conditions such as brain tumors or multiple sclerosis were excluded.

ARIC participants who presented in person for visits 2, 4, 5, and 6 underwent cognitive testing with the Delayed Word Recall Test, the Digit Symbol Substitution Test, and the Word Fluency Test.

Testing at visits 5 and 6 also included other tests, such as the Mini-Mental State Examination, the Boston Naming test, and the Wechsler Memory Scale-III. Dr. Johnson and colleagues excluded data for visit 7 from the analysis because dementia adjudication was not yet complete.

The researchers identified participants with dementia using data from visits 5 and 6 and ascertained time of dementia onset through participant and informant interviews, phone calls, and hospital discharge data. Participants also were screened for mild cognitive impairment (MCI) at visits 5 and 6.

Data were analyzed using a Cox proportional hazards model and multinomial logistic regression. In subsequent analyses, researchers adjusted the data for age, sex, race, smoking status, alcohol use, hypertension, diabetes, body mass index (BMI), APOE4 status, and prevalent stroke.

The researchers found that of 9,033 study participants, 671 had late-onset epilepsy. The late-onset epilepsy group was older at baseline (56.5 vs. 55.1 years) and more likely to have hypertension (38.9% vs. 33.3%), diabetes (16.1% vs. 9.6%), and two alleles of APOE4 genotype (3.9% vs. 2.5%), compared with those without the disorder.

In all, 1,687 participants developed dementia during follow-up. The rate of incident dementia was 41.6% in participants with late-onset epilepsy and 16.8% in participants without late-onset epilepsy. The adjusted hazard ratio of subsequent dementia in participants with late-onset epilepsy versus those without the disorder was 3.05 (95% confidence interval, 2.65-3.51).

The median time to dementia ascertainment after late-onset epilepsy was 3.66 years.
 

Counterintuitive finding

The relationship between late-onset epilepsy and subsequent dementia was stronger in patients without stroke. The investigators offered a possible explanation for this counterintuitive finding. “We observed an interaction between [late-onset epilepsy] and stroke, with a lower (but still substantial) association between [late-onset epilepsy] and dementia in those with a history of stroke. This may be due to the known strong association between stroke and dementia, which may wash out the contributions of [late-onset epilepsy] to cognitive impairment,” the researchers wrote.

“There may also be under-capturing of dementia diagnoses among participants with stroke in the ascertainment from [Centers for Medicare & Medicaid Services] codes, as physicians may be reluctant to make a separate code for ‘dementia’ in those with cognitive impairment after stroke,” they added.

When the researchers restricted the analysis only to participants who attended visits 5 and 6 and had late-onset epilepsy ascertainment available, they found that the relative risk ratio for dementia at visit 6 was 2.90 (95% CI, 1.22-6.92; P = .009). The RRR for MCI was 0.97 (95% CI, 0.39-2.38; P = .803). The greater functional impairment in patients with late-onset epilepsy may explain the lack of a relationship between late-onset epilepsy and MCI.

“It will be important for neurologists to be aware of the possibility of cognitive impairment following late-onset epilepsy and to check in with patients and family members to see if there are concerns,” said Dr. Johnson.

“We should also be talking about the importance of lowering other risk factors for dementia by making sure cardiovascular risk factors are controlled and encouraging physical and cognitive activity,” she added.

The results require confirmation in a clinical population, the investigators noted. In addition, future research is necessary to clarify whether seizures directly increase the risk of dementia or whether shared neuropathology between epilepsy and dementia explains the risk.

“In the near future, I plan to enroll participants with late-onset epilepsy in an observational study to better understand factors that may contribute to cognitive change. Collaborations will be key as we seek to further understand what causes these changes and what could be done to prevent them,” Dr. Johnson added.
 

Strengths and weaknesses

In an accompanying editorial, W. Allen Hauser, MD, professor emeritus of neurology and epidemiology at Columbia University in New York, and colleagues noted that the findings support a bidirectional relationship between dementia and epilepsy, adding that accumulation of amyloid beta peptide is a plausible underlying pathophysiology that may explain this relationship.

Future research should clarify the effect of factors such as seizure type, seizure frequency, and age of onset on the risk of dementia among patients with epilepsy, the editorialists wrote. Such investigations could help elucidate the underlying mechanisms of these conditions and help to improve treatment, they added.

Commenting on the findings, Ilo Leppik, MD, professor of neurology and pharmacy at the University of Minnesota in Minneapolis described the research as “a very well-done study by qualified researchers in the field. … For the last century, medicine has unfortunately become compartmentalized by specialty and then subspecialty. The brain and disorders of the brain do not recognize these silos. … It is not a stretch of the known science to begin to understand that epilepsy and dementia have common anatomical and physiological underpinnings.”

The long period of prospectively gathering data and the measurement of cognitive function through various modalities are among the study’s great strengths, said Dr. Leppik. However, the study’s weakness is its reliance on Medicare claims data, which mainly would reflect convulsive seizures.

“What is missing is how many persons had subtle focal-unaware seizures that may not be identified unless a careful history is taken,” said Dr. Leppik. “Thus, this study likely underestimates the frequency of epilepsy.”

Neurologists who evaluate a person with early dementia should be on the lookout for a history of subtle seizures, said Dr. Leppik. Animal studies suggest treatment with levetiracetam or brivaracetam may slow the course of dementia, and a clinical study in participants with early dementia is underway.

“Treatment with an antiseizure drug may prove to be beneficial, especially if evidence for the presence of subtle epilepsy can be found,” Dr. Leppik added.

Greater collaboration between epileptologists and dementia specialists and larger studies of antiseizure drugs are necessary, he noted. “These studies can incorporate sophisticated structural and biochemical [analyses] to better identify the relationships between brain mechanisms that likely underlie both seizures and dementia. The ultimate promise is that early treatment of seizures may alter the course of dementia,” Dr. Leppik said.

The study by Dr. Johnson and colleagues was supported by a contract from the National Institute on Aging; ARIC from the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the Department of Health & Human Services. The authors and Dr. Leppik have disclosed no relevant financial relationships.

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

A gene-replacement therapy called AT132 significantly decreases dependence on a ventilator among children with X-linked myotubular myopathy, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.

belchonock/Thinkstock

The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.

X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
 

The ASPIRO trial

Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.

Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 10¹⁴ vg/kg of AAT132, 3 × 10¹⁴ vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.

The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
 

Treatment improved respiratory function

As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.

Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.

Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 10¹⁴ vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 10¹⁴ vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.

In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH₂O for the low-dose group, 46.1 cmH₂O for the high-dose group, and −8.0 cmH₂O for controls.

Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.

Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
 

Deaths under investigation

In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.

“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.

Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.

[email protected]

SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.

A gene-replacement therapy called AT132 significantly decreases dependence on a ventilator among children with X-linked myotubular myopathy, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.

belchonock/Thinkstock

The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.

X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
 

The ASPIRO trial

Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.

Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 10¹⁴ vg/kg of AAT132, 3 × 10¹⁴ vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.

The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
 

Treatment improved respiratory function

As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.

Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.

Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 10¹⁴ vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 10¹⁴ vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.

In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH₂O for the low-dose group, 46.1 cmH₂O for the high-dose group, and −8.0 cmH₂O for controls.

Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.

Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
 

Deaths under investigation

In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.

“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.

Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.

[email protected]

SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.

A gene-replacement therapy called AT132 significantly decreases dependence on a ventilator among children with X-linked myotubular myopathy, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, which was held virtually this year. The treatment also appears to improve patients’ motor function significantly and help them to achieve motor milestones.

belchonock/Thinkstock

The results come from a phase 1/2 study of two doses of AT132. Three of 17 patients who received the higher dose had fatal liver dysfunction. The researchers are investigating these cases and will communicate their findings.

X-linked myotubular myopathy is a rare and often fatal neuromuscular disease. Mutations in MTM1, which encodes the myotubularin enzyme that is required for the development and function of skeletal muscle, cause the disease, which affects about one in 50,000 to one in 40,000 newborn boys. The disease is associated with profound muscle weakness and impairment of neuromuscular and respiratory function. Patients with X-linked myotubular myopathy achieve motor milestones much later or not at all, and most require a ventilator or a feeding tube. The mortality by age 18 months is approximately 50%.
 

The ASPIRO trial

Investigators theorized that muscle tissue would be an appropriate therapeutic target because it does not display dystrophic or inflammatory changes in most patients. They identified adeno-associated virus AAV8 as a potential carrier for gene therapy, since it targets skeletal muscle effectively.

Nancy L. Kuntz, MD, an attending physician at Ann and Robert H. Lurie Children’s Hospital of Chicago, and colleagues conducted the ASPIRO trial to examine AT132 as a potential treatment for X-linked myotubular myopathy. Eligible patients were younger than 5 years or had previously enrolled in a natural history study of the disease, required ventilator support at baseline, and had no clinically significant underlying liver disease. Patients were randomly assigned to 1 × 10¹⁴ vg/kg of AAT132, 3 × 10¹⁴ vg/kg of AT132, or delayed treatment. Participants assigned to delayed treatment served as the study’s control group.

The study’s primary end points were safety and change in hours of daily ventilator support from baseline to week 24 after dosing. The investigators also examined a respiratory endpoint (i.e., maximal inspiratory pressure [MIP]) and neuromuscular endpoints (i.e., motor milestones, CHOP INTEND score, and muscle biopsy).
 

Treatment improved respiratory function

As of July 28, Dr. Kuntz and colleagues had enrolled 23 patients in the trial. Six participants received the lower dose of therapy, and 17 received the higher dose. Median age was 1.7 years for the low-dose group and 2.6 years for the high-dose group.

Patients assigned to receive the higher dose of therapy received treatment more recently than the low-dose group, and not all of the former have reached 48 weeks since treatment, said Dr. Kuntz. Fewer efficacy data are thus available for the high-dose group.

Each dose of AT132 was associated with a significantly greater decrease from baseline in least squares mean daily hours of ventilator dependence, compared with the control condition. At week 48, the mean reduction was approximately 19 hours/day for patients receiving 1 × 10¹⁴ vg/kg of AAT132 and approximately 13 hours per day for patients receiving 3 × 10¹⁴ vg/kg of AT132. The investigators did not perform a statistical comparison of the two doses because of differing protocols for ventilator weaning between groups. All six patients who received the lower dose achieved ventilator independence, as did one patient who received the higher dose.

In addition, all treated patients had significantly greater increases from baseline in least squares mean MIP, compared with controls. The mean increase was 45.7 cmH₂O for the low-dose group, 46.1 cmH₂O for the high-dose group, and −8.0 cmH₂O for controls.

Before treatment, most patients had not achieved any of the motor milestones that investigators assessed. After treatment, five of six patients receiving the low dose achieved independent walking, as did one in 10 patients receiving the high dose. No controls achieved this milestone. Treated patients also had significantly greater increases from baseline in least squares mean CHOP INTEND scores, compared with controls. At least at one time point, five of six patients receiving the low dose, six of 10 patients receiving the high dose, and one control patient achieved the mean score observed in healthy infants.

Patients in both treatment arms had improvements in muscle pathology at weeks 24 and 48, including improvements in organelle localization and fiber size. In addition, patients in both treatment arms had continued detectable vector copies and myotubularin protein expression at both time points.
 

Deaths under investigation

In the low-dose group, one patient had four serious treatment-emergent adverse events, and in the high-dose group, eight patients had 27 serious treatment-emergent adverse events. The three patients in the high-dose group who developed fatal liver dysfunction were among the older, heavier patients in the study and, consequently, received among the highest total doses of treatment. These patients had evidence of likely preexisting intrahepatic cholestasis.

“This clinical trial is on hold pending discussions between regulatory agencies and the study sponsor regarding additional recruitment and the duration of follow-up,” said Dr. Kuntz.

Audentes Therapeutics, which is developing AT132, funded the trial. Dr. Kuntz had no conflicts of interest.

[email protected]

SOURCE: Bönnemann CG et al. CNS-ICNA 2020, Abstract P.62.

Long-term treatment with ataluren delays loss of ambulation and may delay decline in pulmonary function in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD), according to study results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Because so few patients in the study reached one of the negative pulmonary endpoints, longer follow-up will be needed to assess more conclusively the effect of ataluren on pulmonary function, said Francesco Bibbiani, MD, vice president of clinical development at PTC Therapeutics.

DMD is a rare and fatal neuromuscular disorder that causes progressive muscle weakness. Between 10% and 15% of patients with DMD have a nonsense mutation in the DMD gene. This mutation creates a premature stop codon that prevents the translation of a full-length dystrophin protein. Ataluren is designed to promote readthrough of this premature stop codon, thus enabling the production of a full-length dystrophin protein. An oral formulation of the drug has been approved in several European and South American countries.
 

Comparing treatment and standard of care

Study 019 was a phase 3, multicenter, open-label, long-term safety study of ataluren that enrolled international patients with nmDMD, most of whom had participated previously in a trial of ataluren. Dr. Bibbiani and colleagues conducted a post hoc analysis of Study 019 data to determine whether patients with nmDMD who received ataluren and standard of care for as long as 240 weeks had a different time to loss of ambulation and to decline of pulmonary function, compared with patients who received standard of care alone. Patients who were eligible to participate in Study 019 were male, had nmDMD, and had completed the blinded study drug treatment in a previous PTC-sponsored study. Treatment consisted of two 10-mg/kg doses and one 20-mg/kg dose of ataluren per day.

Dr. Bibbiani and colleagues used participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) as a control group. CINRG DNHS was a prospective, longitudinal study of patients with DMD who received standard of care at 20 centers worldwide from 2006 to 2016. Dr. Bibbiani and colleagues used propensity-score matching to pair participants in this study with participants in Study 019. They matched patients with respect to age at onset of first symptoms, age at initiation of corticosteroid use, duration of deflazacort use, and duration of use of other corticosteroids. These factors are established predictors of disease progression in DMD.

Patients were eligible for inclusion in the post hoc analysis if they had available data for age, loss of ambulation, and the covariates selected for matching. Of 94 Study 019 participants, 60 were eligible for propensity-score matching with participants in CINRG DNHS. Forty-five nonambulatory patients were eligible for matching in the analysis of age at the decline in pulmonary function because data for age at loss of ambulation and for the three pulmonary endpoints measured were available for them. Thus, comparable population sizes were available for each analysis.
 

Treatment delayed disease milestones

Kaplan–Meier analysis indicated that the median age at various disease milestones was higher among patients who received ataluren and standard of care, compared with those who received standard of care alone. The median age at loss of ambulation was 15.5 years for Study 019 participants and 13.3 years for CINRG DNHS patients. The median age at predicted forced vital capacity (FVC) of less than 60% was 18.1 years for Study 019 participants and 15.8 years for CINRG DNHS participants. The median age at predicted FVC of less than 50% was 19.1 years for Study 019 participants and 17.9 years for CINRG DNHS participants. Finally, the median age at FVC of less than 1 L was not calculable for Study 019 participants and 23.8 years for CINRG DNHS participants.

The Study 019 and CINRG DNHS study groups are sponsored by PTC Therapeutics, which developed ataluren. Dr. Bibbiani is an employee of PTC Therapeutics.

[email protected]

SOURCE: McDonald C, et al. CNS-ICNA 2020. Abstract PL69.

Long-term treatment with ataluren delays loss of ambulation and may delay decline in pulmonary function in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD), according to study results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Because so few patients in the study reached one of the negative pulmonary endpoints, longer follow-up will be needed to assess more conclusively the effect of ataluren on pulmonary function, said Francesco Bibbiani, MD, vice president of clinical development at PTC Therapeutics.

DMD is a rare and fatal neuromuscular disorder that causes progressive muscle weakness. Between 10% and 15% of patients with DMD have a nonsense mutation in the DMD gene. This mutation creates a premature stop codon that prevents the translation of a full-length dystrophin protein. Ataluren is designed to promote readthrough of this premature stop codon, thus enabling the production of a full-length dystrophin protein. An oral formulation of the drug has been approved in several European and South American countries.
 

Comparing treatment and standard of care

Study 019 was a phase 3, multicenter, open-label, long-term safety study of ataluren that enrolled international patients with nmDMD, most of whom had participated previously in a trial of ataluren. Dr. Bibbiani and colleagues conducted a post hoc analysis of Study 019 data to determine whether patients with nmDMD who received ataluren and standard of care for as long as 240 weeks had a different time to loss of ambulation and to decline of pulmonary function, compared with patients who received standard of care alone. Patients who were eligible to participate in Study 019 were male, had nmDMD, and had completed the blinded study drug treatment in a previous PTC-sponsored study. Treatment consisted of two 10-mg/kg doses and one 20-mg/kg dose of ataluren per day.

Dr. Bibbiani and colleagues used participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) as a control group. CINRG DNHS was a prospective, longitudinal study of patients with DMD who received standard of care at 20 centers worldwide from 2006 to 2016. Dr. Bibbiani and colleagues used propensity-score matching to pair participants in this study with participants in Study 019. They matched patients with respect to age at onset of first symptoms, age at initiation of corticosteroid use, duration of deflazacort use, and duration of use of other corticosteroids. These factors are established predictors of disease progression in DMD.

Patients were eligible for inclusion in the post hoc analysis if they had available data for age, loss of ambulation, and the covariates selected for matching. Of 94 Study 019 participants, 60 were eligible for propensity-score matching with participants in CINRG DNHS. Forty-five nonambulatory patients were eligible for matching in the analysis of age at the decline in pulmonary function because data for age at loss of ambulation and for the three pulmonary endpoints measured were available for them. Thus, comparable population sizes were available for each analysis.
 

Treatment delayed disease milestones

Kaplan–Meier analysis indicated that the median age at various disease milestones was higher among patients who received ataluren and standard of care, compared with those who received standard of care alone. The median age at loss of ambulation was 15.5 years for Study 019 participants and 13.3 years for CINRG DNHS patients. The median age at predicted forced vital capacity (FVC) of less than 60% was 18.1 years for Study 019 participants and 15.8 years for CINRG DNHS participants. The median age at predicted FVC of less than 50% was 19.1 years for Study 019 participants and 17.9 years for CINRG DNHS participants. Finally, the median age at FVC of less than 1 L was not calculable for Study 019 participants and 23.8 years for CINRG DNHS participants.

The Study 019 and CINRG DNHS study groups are sponsored by PTC Therapeutics, which developed ataluren. Dr. Bibbiani is an employee of PTC Therapeutics.

[email protected]

SOURCE: McDonald C, et al. CNS-ICNA 2020. Abstract PL69.

Long-term treatment with ataluren delays loss of ambulation and may delay decline in pulmonary function in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD), according to study results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Because so few patients in the study reached one of the negative pulmonary endpoints, longer follow-up will be needed to assess more conclusively the effect of ataluren on pulmonary function, said Francesco Bibbiani, MD, vice president of clinical development at PTC Therapeutics.

DMD is a rare and fatal neuromuscular disorder that causes progressive muscle weakness. Between 10% and 15% of patients with DMD have a nonsense mutation in the DMD gene. This mutation creates a premature stop codon that prevents the translation of a full-length dystrophin protein. Ataluren is designed to promote readthrough of this premature stop codon, thus enabling the production of a full-length dystrophin protein. An oral formulation of the drug has been approved in several European and South American countries.
 

Comparing treatment and standard of care

Study 019 was a phase 3, multicenter, open-label, long-term safety study of ataluren that enrolled international patients with nmDMD, most of whom had participated previously in a trial of ataluren. Dr. Bibbiani and colleagues conducted a post hoc analysis of Study 019 data to determine whether patients with nmDMD who received ataluren and standard of care for as long as 240 weeks had a different time to loss of ambulation and to decline of pulmonary function, compared with patients who received standard of care alone. Patients who were eligible to participate in Study 019 were male, had nmDMD, and had completed the blinded study drug treatment in a previous PTC-sponsored study. Treatment consisted of two 10-mg/kg doses and one 20-mg/kg dose of ataluren per day.

Dr. Bibbiani and colleagues used participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) as a control group. CINRG DNHS was a prospective, longitudinal study of patients with DMD who received standard of care at 20 centers worldwide from 2006 to 2016. Dr. Bibbiani and colleagues used propensity-score matching to pair participants in this study with participants in Study 019. They matched patients with respect to age at onset of first symptoms, age at initiation of corticosteroid use, duration of deflazacort use, and duration of use of other corticosteroids. These factors are established predictors of disease progression in DMD.

Patients were eligible for inclusion in the post hoc analysis if they had available data for age, loss of ambulation, and the covariates selected for matching. Of 94 Study 019 participants, 60 were eligible for propensity-score matching with participants in CINRG DNHS. Forty-five nonambulatory patients were eligible for matching in the analysis of age at the decline in pulmonary function because data for age at loss of ambulation and for the three pulmonary endpoints measured were available for them. Thus, comparable population sizes were available for each analysis.
 

Treatment delayed disease milestones

Kaplan–Meier analysis indicated that the median age at various disease milestones was higher among patients who received ataluren and standard of care, compared with those who received standard of care alone. The median age at loss of ambulation was 15.5 years for Study 019 participants and 13.3 years for CINRG DNHS patients. The median age at predicted forced vital capacity (FVC) of less than 60% was 18.1 years for Study 019 participants and 15.8 years for CINRG DNHS participants. The median age at predicted FVC of less than 50% was 19.1 years for Study 019 participants and 17.9 years for CINRG DNHS participants. Finally, the median age at FVC of less than 1 L was not calculable for Study 019 participants and 23.8 years for CINRG DNHS participants.

The Study 019 and CINRG DNHS study groups are sponsored by PTC Therapeutics, which developed ataluren. Dr. Bibbiani is an employee of PTC Therapeutics.

[email protected]

SOURCE: McDonald C, et al. CNS-ICNA 2020. Abstract PL69.

Among patients with pediatric-onset relapsing-remitting multiple sclerosis (MS), newer disease-modifying therapies (DMTs) reduce clinical and radiological disease activity more effectively than older injectable therapies. Nevertheless, all DMTs reduce children’s annualized relapse rate (ARR), according to results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Our study adds weight to the argument for an imminent shift in clinical practice toward the use of newer, more efficacious DMTs in the first instance,” said Omar Abdel-Mannan, MD, of Great Ormond Street Hospital in London. MRI activity continues among patients treated with DMTs, and the number of relapses is highest in the period following diagnosis. But because the effect of treatment on brain atrophy is greatest in the initial period of disease, “this time period may represent a critical therapeutic window for the use of highly effective therapies,” said Dr. Abdel-Mannan.
 

An examination of medical records

MS is much less prevalent among children than among adults. Compared with adults with MS, children with MS have a higher relapse rate and slower accumulation of disability. The individual response to DMTs is variable, said Dr. Abdel-Mannan. Furthermore, current standards of care for pediatric MS vary by center and are based on adult protocols.

Dr. Abdel-Mannan and colleagues conducted a retrospective study to evaluate the real-world effectiveness of the newer oral and infusion DMTs, compared with the older injectable DMTs, in children with relapsing-remitting MS. They examined data from seven tertiary pediatric neurology centers in the United Kingdom and identified patients under age 18 years with relapsing-remitting MS who were treated with DMTs between 2012 and 2018. The investigators reviewed clinical and paraclinical data retrospectively using electronic medical records. They compared patients’ ARR, new radiological activity, and Expanded Disability Status Scale score pretreatment and on treatment.

The researchers included 103 patients in their analysis. The population’s median age was 14 years. The ratio of girls to boys was approximately 3:1. Whites and other races/ethnicities accounted for approximately equal groups of patients. About one-third of patients presented with a clinically isolated syndrome (CIS) in the form of transverse myelitis or optic neuritis. Two-thirds presented with other CIS phenotypes. Almost all children had an abnormal MRI at onset.
 

Most patients initiated injectable DMTs

Of the 103 patients, 89 started treatment with an injectable (e.g., glatiramer or interferon) or an older DMT. Fourteen patients began treatment with a newer DMT (e.g., dimethyl fumarate, fingolimod, natalizumab, and alemtuzumab). Three of the 89 patients on an injectable DMT switched to another injectable DMT, and two of these patients later escalated to a newer DMT. Thirty-five of the 89 patients who initiated an injectable DMT were escalated immediately to a newer DMT. One of these patients later switched to another newer DMT. Two of the 14 patients who started on a newer DMT as their first drug switched to another newer DMT.

The investigators observed a reduction in ARR for all DMTs used during the study period. Nevertheless, a significant number of patients receiving injectable DMTs continued to relapse on treatment. Almost all patients receiving newer DMTs, however, had a reduction in relapses. When Dr. Abdel-Mannan and colleagues performed Kaplan–Meier survival analysis, they found that patients receiving newer DMTs had a longer time to first relapse and a longer time to switch treatment over 2 years, compared with patients receiving injectable DMTs. In addition, patients receiving newer DMTs had a longer time to develop new radiological activity, compared with patients receiving injectables. The analysis also indicated that the proportion of patients with new radiological activity was higher than the proportion who had clinical relapses and an Expanded Disability Status Scale score increase of more than 1 point over 2 years.

In all, 55 of the children receiving injectable DMTs and 18 of the patients receiving newer DMTs had side effects. The most commonly reported side effects were flulike symptoms and injection-site reactions. Five patients discontinued or switched their DMTs because of side effects. “Reassuringly, no pediatric-specific side effects were reported,” said Dr. Abdel-Mannan. The newer DMTs had similar short-term safety, tolerability, and side-effect profiles in these children as in adult patients.

The study was conducted on behalf of the UK Childhood Inflammatory Demyelination Network. Dr. Abdel-Mannan had no relevant disclosures.

[email protected]

SOURCE: Abdel-Mannan O et al. CNS-ICNA 2020, Abstract PL10.

Among patients with pediatric-onset relapsing-remitting multiple sclerosis (MS), newer disease-modifying therapies (DMTs) reduce clinical and radiological disease activity more effectively than older injectable therapies. Nevertheless, all DMTs reduce children’s annualized relapse rate (ARR), according to results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Our study adds weight to the argument for an imminent shift in clinical practice toward the use of newer, more efficacious DMTs in the first instance,” said Omar Abdel-Mannan, MD, of Great Ormond Street Hospital in London. MRI activity continues among patients treated with DMTs, and the number of relapses is highest in the period following diagnosis. But because the effect of treatment on brain atrophy is greatest in the initial period of disease, “this time period may represent a critical therapeutic window for the use of highly effective therapies,” said Dr. Abdel-Mannan.
 

An examination of medical records

MS is much less prevalent among children than among adults. Compared with adults with MS, children with MS have a higher relapse rate and slower accumulation of disability. The individual response to DMTs is variable, said Dr. Abdel-Mannan. Furthermore, current standards of care for pediatric MS vary by center and are based on adult protocols.

Dr. Abdel-Mannan and colleagues conducted a retrospective study to evaluate the real-world effectiveness of the newer oral and infusion DMTs, compared with the older injectable DMTs, in children with relapsing-remitting MS. They examined data from seven tertiary pediatric neurology centers in the United Kingdom and identified patients under age 18 years with relapsing-remitting MS who were treated with DMTs between 2012 and 2018. The investigators reviewed clinical and paraclinical data retrospectively using electronic medical records. They compared patients’ ARR, new radiological activity, and Expanded Disability Status Scale score pretreatment and on treatment.

The researchers included 103 patients in their analysis. The population’s median age was 14 years. The ratio of girls to boys was approximately 3:1. Whites and other races/ethnicities accounted for approximately equal groups of patients. About one-third of patients presented with a clinically isolated syndrome (CIS) in the form of transverse myelitis or optic neuritis. Two-thirds presented with other CIS phenotypes. Almost all children had an abnormal MRI at onset.
 

Most patients initiated injectable DMTs

Of the 103 patients, 89 started treatment with an injectable (e.g., glatiramer or interferon) or an older DMT. Fourteen patients began treatment with a newer DMT (e.g., dimethyl fumarate, fingolimod, natalizumab, and alemtuzumab). Three of the 89 patients on an injectable DMT switched to another injectable DMT, and two of these patients later escalated to a newer DMT. Thirty-five of the 89 patients who initiated an injectable DMT were escalated immediately to a newer DMT. One of these patients later switched to another newer DMT. Two of the 14 patients who started on a newer DMT as their first drug switched to another newer DMT.

The investigators observed a reduction in ARR for all DMTs used during the study period. Nevertheless, a significant number of patients receiving injectable DMTs continued to relapse on treatment. Almost all patients receiving newer DMTs, however, had a reduction in relapses. When Dr. Abdel-Mannan and colleagues performed Kaplan–Meier survival analysis, they found that patients receiving newer DMTs had a longer time to first relapse and a longer time to switch treatment over 2 years, compared with patients receiving injectable DMTs. In addition, patients receiving newer DMTs had a longer time to develop new radiological activity, compared with patients receiving injectables. The analysis also indicated that the proportion of patients with new radiological activity was higher than the proportion who had clinical relapses and an Expanded Disability Status Scale score increase of more than 1 point over 2 years.

In all, 55 of the children receiving injectable DMTs and 18 of the patients receiving newer DMTs had side effects. The most commonly reported side effects were flulike symptoms and injection-site reactions. Five patients discontinued or switched their DMTs because of side effects. “Reassuringly, no pediatric-specific side effects were reported,” said Dr. Abdel-Mannan. The newer DMTs had similar short-term safety, tolerability, and side-effect profiles in these children as in adult patients.

The study was conducted on behalf of the UK Childhood Inflammatory Demyelination Network. Dr. Abdel-Mannan had no relevant disclosures.

[email protected]

SOURCE: Abdel-Mannan O et al. CNS-ICNA 2020, Abstract PL10.

Among patients with pediatric-onset relapsing-remitting multiple sclerosis (MS), newer disease-modifying therapies (DMTs) reduce clinical and radiological disease activity more effectively than older injectable therapies. Nevertheless, all DMTs reduce children’s annualized relapse rate (ARR), according to results presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Our study adds weight to the argument for an imminent shift in clinical practice toward the use of newer, more efficacious DMTs in the first instance,” said Omar Abdel-Mannan, MD, of Great Ormond Street Hospital in London. MRI activity continues among patients treated with DMTs, and the number of relapses is highest in the period following diagnosis. But because the effect of treatment on brain atrophy is greatest in the initial period of disease, “this time period may represent a critical therapeutic window for the use of highly effective therapies,” said Dr. Abdel-Mannan.
 

An examination of medical records

MS is much less prevalent among children than among adults. Compared with adults with MS, children with MS have a higher relapse rate and slower accumulation of disability. The individual response to DMTs is variable, said Dr. Abdel-Mannan. Furthermore, current standards of care for pediatric MS vary by center and are based on adult protocols.

Dr. Abdel-Mannan and colleagues conducted a retrospective study to evaluate the real-world effectiveness of the newer oral and infusion DMTs, compared with the older injectable DMTs, in children with relapsing-remitting MS. They examined data from seven tertiary pediatric neurology centers in the United Kingdom and identified patients under age 18 years with relapsing-remitting MS who were treated with DMTs between 2012 and 2018. The investigators reviewed clinical and paraclinical data retrospectively using electronic medical records. They compared patients’ ARR, new radiological activity, and Expanded Disability Status Scale score pretreatment and on treatment.

The researchers included 103 patients in their analysis. The population’s median age was 14 years. The ratio of girls to boys was approximately 3:1. Whites and other races/ethnicities accounted for approximately equal groups of patients. About one-third of patients presented with a clinically isolated syndrome (CIS) in the form of transverse myelitis or optic neuritis. Two-thirds presented with other CIS phenotypes. Almost all children had an abnormal MRI at onset.
 

Most patients initiated injectable DMTs

Of the 103 patients, 89 started treatment with an injectable (e.g., glatiramer or interferon) or an older DMT. Fourteen patients began treatment with a newer DMT (e.g., dimethyl fumarate, fingolimod, natalizumab, and alemtuzumab). Three of the 89 patients on an injectable DMT switched to another injectable DMT, and two of these patients later escalated to a newer DMT. Thirty-five of the 89 patients who initiated an injectable DMT were escalated immediately to a newer DMT. One of these patients later switched to another newer DMT. Two of the 14 patients who started on a newer DMT as their first drug switched to another newer DMT.

The investigators observed a reduction in ARR for all DMTs used during the study period. Nevertheless, a significant number of patients receiving injectable DMTs continued to relapse on treatment. Almost all patients receiving newer DMTs, however, had a reduction in relapses. When Dr. Abdel-Mannan and colleagues performed Kaplan–Meier survival analysis, they found that patients receiving newer DMTs had a longer time to first relapse and a longer time to switch treatment over 2 years, compared with patients receiving injectable DMTs. In addition, patients receiving newer DMTs had a longer time to develop new radiological activity, compared with patients receiving injectables. The analysis also indicated that the proportion of patients with new radiological activity was higher than the proportion who had clinical relapses and an Expanded Disability Status Scale score increase of more than 1 point over 2 years.

In all, 55 of the children receiving injectable DMTs and 18 of the patients receiving newer DMTs had side effects. The most commonly reported side effects were flulike symptoms and injection-site reactions. Five patients discontinued or switched their DMTs because of side effects. “Reassuringly, no pediatric-specific side effects were reported,” said Dr. Abdel-Mannan. The newer DMTs had similar short-term safety, tolerability, and side-effect profiles in these children as in adult patients.

The study was conducted on behalf of the UK Childhood Inflammatory Demyelination Network. Dr. Abdel-Mannan had no relevant disclosures.

[email protected]

SOURCE: Abdel-Mannan O et al. CNS-ICNA 2020, Abstract PL10.

Among children with persistent postconcussion symptoms, poor recovery at 10 weeks is associated with higher cerebral blood flow at 4-6 weeks, according to a study presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Furthermore, cerebral blood flow at 4-6 weeks predicts recovery during the next 4 weeks in 77% of children.

“This is the first study to examine cerebral blood flow changes in children with persistent postconcussion symptoms,” said Karen Barlow, MBChB, associate professor of biomedical sciences at the University of Queensland in St. Lucia, Australia. “Our findings support the link between neurovascular unit dysfunction and persistent postconcussion symptoms in children, potentially because of injury or dysfunction in the GABAergic interneurons.”
 

Quantifying cerebral tissue perfusion

At least 25% of children with concussion have persistent postconcussion symptoms at 1 month post injury. Understanding the factors that influence the speed of recovery may help clarify the biology of postconcussion symptoms and suggest new treatments. In previous research, Dr. Barlow and colleagues found that children with early recovery (i.e., recovery by 4 weeks post injury) have decreases in cerebral blood flow, when compared with normal children. Children with persistent symptoms, however, have increases in cerebral blood flow. Dr. Barlow and colleagues conducted a new study to examine how cerebral blood flow changes in children with persistent postconcussion symptoms.

The investigators recruited participants through the randomized controlled Play Game trial, which examined melatonin as a treatment for persistent postconcussion symptoms. Among the exclusion criteria were history of assault, drug or alcohol use, significant past medical or psychiatric history, concussion within the previous 3 months, and use of psychoactive medications.

Children entered the study at 4-8 weeks after injury and received treatment for 4 weeks. Participants underwent 3-D pseudo-continuous arterial spin–labeled MRI before and after the treatment period (i.e., at 5 and 10 weeks post injury). This imaging technique provides a quantitative assessment of cerebral tissue perfusion. “You can do it without manipulating the cerebral circulation, making it particularly useful for research and in children,” said Dr. Barlow.

She and her colleagues evaluated recovery using the Post-Concussion Symptom Inventory. They defined good recovery as a total score at or below baseline at 10 weeks post injury. They considered any children who did not meet this criterion to have poor recovery.
 

Speed of blood-flow change varied

In all, 124 children were eligible for the study, and 76 had MRIs at both time points. Fourteen participants were excluded because of motion artifacts, slice truncation, and normalization failure. The population’s average age was approximately 14 years. About half of participants were males. The first MRI was performed at 37 days post injury, and the second MRI at around 70 days post injury. Twenty-three children had good recovery.

Children with poor recovery at 10 weeks had higher relative cerebral blood flow, compared with children with good recovery. Treatment group, age, and sex did not affect the changes in relative cerebral blood flow over time. Dr. Barlow and colleagues also measured mean total gray matter cerebral blood flow. Children with poor recovery had higher cerebral blood flow at 5 and 10 weeks post injury, compared with children with good recovery. In addition, cerebral blood flow changed more slowly in participants with poor recovery, compared with those with good recovery. Logistic regression analysis indicated that the mean absolute gray matter cerebral blood flow at 4-6 weeks post injury significantly predicted which children would recover by 10 weeks post injury, with an area under the receiver operating characteristic curve of 77%.

Funders for the study included Alberta Children’s Hospital, the Canadian Institutes of Health Research, and the University of Calgary. Dr. Barlow had no disclosures or conflicts of interest.

[email protected]

SOURCE: Barlow K et al. CNS-ICNA 2020. Abstract PL100.

Among children with persistent postconcussion symptoms, poor recovery at 10 weeks is associated with higher cerebral blood flow at 4-6 weeks, according to a study presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Furthermore, cerebral blood flow at 4-6 weeks predicts recovery during the next 4 weeks in 77% of children.

“This is the first study to examine cerebral blood flow changes in children with persistent postconcussion symptoms,” said Karen Barlow, MBChB, associate professor of biomedical sciences at the University of Queensland in St. Lucia, Australia. “Our findings support the link between neurovascular unit dysfunction and persistent postconcussion symptoms in children, potentially because of injury or dysfunction in the GABAergic interneurons.”
 

Quantifying cerebral tissue perfusion

At least 25% of children with concussion have persistent postconcussion symptoms at 1 month post injury. Understanding the factors that influence the speed of recovery may help clarify the biology of postconcussion symptoms and suggest new treatments. In previous research, Dr. Barlow and colleagues found that children with early recovery (i.e., recovery by 4 weeks post injury) have decreases in cerebral blood flow, when compared with normal children. Children with persistent symptoms, however, have increases in cerebral blood flow. Dr. Barlow and colleagues conducted a new study to examine how cerebral blood flow changes in children with persistent postconcussion symptoms.

The investigators recruited participants through the randomized controlled Play Game trial, which examined melatonin as a treatment for persistent postconcussion symptoms. Among the exclusion criteria were history of assault, drug or alcohol use, significant past medical or psychiatric history, concussion within the previous 3 months, and use of psychoactive medications.

Children entered the study at 4-8 weeks after injury and received treatment for 4 weeks. Participants underwent 3-D pseudo-continuous arterial spin–labeled MRI before and after the treatment period (i.e., at 5 and 10 weeks post injury). This imaging technique provides a quantitative assessment of cerebral tissue perfusion. “You can do it without manipulating the cerebral circulation, making it particularly useful for research and in children,” said Dr. Barlow.

She and her colleagues evaluated recovery using the Post-Concussion Symptom Inventory. They defined good recovery as a total score at or below baseline at 10 weeks post injury. They considered any children who did not meet this criterion to have poor recovery.
 

Speed of blood-flow change varied

In all, 124 children were eligible for the study, and 76 had MRIs at both time points. Fourteen participants were excluded because of motion artifacts, slice truncation, and normalization failure. The population’s average age was approximately 14 years. About half of participants were males. The first MRI was performed at 37 days post injury, and the second MRI at around 70 days post injury. Twenty-three children had good recovery.

Children with poor recovery at 10 weeks had higher relative cerebral blood flow, compared with children with good recovery. Treatment group, age, and sex did not affect the changes in relative cerebral blood flow over time. Dr. Barlow and colleagues also measured mean total gray matter cerebral blood flow. Children with poor recovery had higher cerebral blood flow at 5 and 10 weeks post injury, compared with children with good recovery. In addition, cerebral blood flow changed more slowly in participants with poor recovery, compared with those with good recovery. Logistic regression analysis indicated that the mean absolute gray matter cerebral blood flow at 4-6 weeks post injury significantly predicted which children would recover by 10 weeks post injury, with an area under the receiver operating characteristic curve of 77%.

Funders for the study included Alberta Children’s Hospital, the Canadian Institutes of Health Research, and the University of Calgary. Dr. Barlow had no disclosures or conflicts of interest.

[email protected]

SOURCE: Barlow K et al. CNS-ICNA 2020. Abstract PL100.

Among children with persistent postconcussion symptoms, poor recovery at 10 weeks is associated with higher cerebral blood flow at 4-6 weeks, according to a study presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. Furthermore, cerebral blood flow at 4-6 weeks predicts recovery during the next 4 weeks in 77% of children.

“This is the first study to examine cerebral blood flow changes in children with persistent postconcussion symptoms,” said Karen Barlow, MBChB, associate professor of biomedical sciences at the University of Queensland in St. Lucia, Australia. “Our findings support the link between neurovascular unit dysfunction and persistent postconcussion symptoms in children, potentially because of injury or dysfunction in the GABAergic interneurons.”
 

Quantifying cerebral tissue perfusion

At least 25% of children with concussion have persistent postconcussion symptoms at 1 month post injury. Understanding the factors that influence the speed of recovery may help clarify the biology of postconcussion symptoms and suggest new treatments. In previous research, Dr. Barlow and colleagues found that children with early recovery (i.e., recovery by 4 weeks post injury) have decreases in cerebral blood flow, when compared with normal children. Children with persistent symptoms, however, have increases in cerebral blood flow. Dr. Barlow and colleagues conducted a new study to examine how cerebral blood flow changes in children with persistent postconcussion symptoms.

The investigators recruited participants through the randomized controlled Play Game trial, which examined melatonin as a treatment for persistent postconcussion symptoms. Among the exclusion criteria were history of assault, drug or alcohol use, significant past medical or psychiatric history, concussion within the previous 3 months, and use of psychoactive medications.

Children entered the study at 4-8 weeks after injury and received treatment for 4 weeks. Participants underwent 3-D pseudo-continuous arterial spin–labeled MRI before and after the treatment period (i.e., at 5 and 10 weeks post injury). This imaging technique provides a quantitative assessment of cerebral tissue perfusion. “You can do it without manipulating the cerebral circulation, making it particularly useful for research and in children,” said Dr. Barlow.

She and her colleagues evaluated recovery using the Post-Concussion Symptom Inventory. They defined good recovery as a total score at or below baseline at 10 weeks post injury. They considered any children who did not meet this criterion to have poor recovery.
 

Speed of blood-flow change varied

In all, 124 children were eligible for the study, and 76 had MRIs at both time points. Fourteen participants were excluded because of motion artifacts, slice truncation, and normalization failure. The population’s average age was approximately 14 years. About half of participants were males. The first MRI was performed at 37 days post injury, and the second MRI at around 70 days post injury. Twenty-three children had good recovery.

Children with poor recovery at 10 weeks had higher relative cerebral blood flow, compared with children with good recovery. Treatment group, age, and sex did not affect the changes in relative cerebral blood flow over time. Dr. Barlow and colleagues also measured mean total gray matter cerebral blood flow. Children with poor recovery had higher cerebral blood flow at 5 and 10 weeks post injury, compared with children with good recovery. In addition, cerebral blood flow changed more slowly in participants with poor recovery, compared with those with good recovery. Logistic regression analysis indicated that the mean absolute gray matter cerebral blood flow at 4-6 weeks post injury significantly predicted which children would recover by 10 weeks post injury, with an area under the receiver operating characteristic curve of 77%.

Funders for the study included Alberta Children’s Hospital, the Canadian Institutes of Health Research, and the University of Calgary. Dr. Barlow had no disclosures or conflicts of interest.

[email protected]

SOURCE: Barlow K et al. CNS-ICNA 2020. Abstract PL100.

Nusinersen provides continued, long-term benefits to infants with spinal muscular atrophy (SMA) who begin treatment before symptom onset, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”

Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
 

An ongoing open-label study

Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.

The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
 

Treatment improved motor development

Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.

Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.

Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.

Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.

[email protected]

SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.

Nusinersen provides continued, long-term benefits to infants with spinal muscular atrophy (SMA) who begin treatment before symptom onset, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”

Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
 

An ongoing open-label study

Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.

The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
 

Treatment improved motor development

Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.

Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.

Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.

Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.

[email protected]

SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.

Nusinersen provides continued, long-term benefits to infants with spinal muscular atrophy (SMA) who begin treatment before symptom onset, according to an analysis presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year.

“Children are developing in a manner more consistent with normal development than that expected for children with two and three SMN2 gene copies,” said Russell Chin, MD, a neurologist at New York–Presbyterian Hospital. “These data demonstrate the durability of effect over a median of 3.8 years of follow-up, with children aged 2.8-4.8 years at the last visit.”

Many participants in the study achieved motor milestones within normal time limits, and no participant lost any major motor milestones. The investigators did not identify any new safety concerns during a maximum of 4.7 years of follow-up. They will follow participants until they reach approximately 8 years of age.
 

An ongoing open-label study

Dr. Chin presented interim results of the ongoing NURTURE study, which is examining the efficacy and safety of intrathecal nusinersen when administered to presymptomatic infants with SMA. The open-label, single-arm, phase 2 study is being conducted in various countries. Eligible participants were 6 weeks old or younger at first dose and had two or three copies of SMN2. The primary end point of NURTURE is time to death or respiratory intervention (i.e., invasive or noninvasive ventilation for 6 or more hours per day continuously for 7 or more days or tracheostomy). The natural history of SMA type 1 indicates that the median age at death or requirement for ventilation support is 13.5 months.

The investigators enrolled 25 infants: 15 with two copies of the gene and 10 with three copies. At the February 2020 interim analysis, participants had been in the study for 3.8 years and were aged 2.8-4.8 years at the last visit. No children had discontinued treatment or withdrawn from the study. All participants are alive, and four participants (all of whom have two copies of SMN2) required respiratory intervention. The latter children initiated respiratory support during an acute reversible illness. No subjects have required permanent ventilation, which the investigators define as ventilation for 16 or more hours per day for more than 21 days in the absence of an acute reversible event, or tracheostomy.
 

Treatment improved motor development

Approximately 84% of children achieved a maximum score on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale. The population’s mean CHOP INTEND score increased steadily from baseline and stabilized at approximately the maximum score of 64. The population’s mean change in CHOP INTEND score from baseline to last visit was 13.6 points. The mean score at last visit was 62.0 among patients with two copies of SMN2 and 63.4 among patients with three copies. In addition, the time to first achievement of maximum CHOP INTEND score was shorter in participants with three copies of SMN2, compared with those with two. Four participants with two copies of the gene have not yet achieved a maximum CHOP INTEND score.

Many of the children in the study achieved World Health Organization motor milestones within time frames consistent with normal development. About 84% of participants became able to sit without support within the normal time frame in healthy children. Approximately 60% of children achieved walking with assistance within the normal window, and 64% achieved walking alone within the normal window. Of 25 participants, 24 are walking with assistance, and 22 of 25 (88%) can walk alone. Dr. Chin and colleagues observed that lower levels of phosphorylated neurofilament heavy chain in plasma and cerebrospinal fluid on treatment at day 64 were significantly correlated with higher total score on the Hammersmith Infant Neurological Examination at day 302 and with earlier achievement of the WHO milestone walking alone.

Nusinersen and lumbar puncture were well tolerated. No children discontinued treatment or withdrew from the study because of an adverse event. The investigators did not consider any adverse events or serious adverse events to be related to the study drug. They also did not observe any clinically relevant trends related to nusinersen in hematology, blood chemistry, urinalysis, coagulation, vital signs, or ECGs.

Dr. Chin is an employee of and holds stock in Biogen, which manufactures nusinersen and is sponsoring the study.

[email protected]

SOURCE: Chin R et al. CNS-ICNA 2020, Abstract PL78.

Neutrophil granulocyte biomarkers can distinguish between neuromyelitis optica spectrum disorders (NMOSD) and anti-MOG antibody–associated disease (MOGAD) on one hand and multiple sclerosis (MS) on the other hand, researchers reported. If current findings are replicated, these biomarkers will help neurologists distinguish between these disorders in the future, even in cases that are negative for autoantibodies, they said.

The sensitivity and specificity profile of neutrophil granulocyte biomarkers is not as good as that for cell-based assays for AQP4 and anti-MOG antibodies when it comes to distinguishing between acute NMOSD or MOGAD versus acute relapsing-remitting MS, said David Leppert, MD, of University Hospital Basel (Switzerland) and the University of Basel. But the sensitivity and specificity of neutrophil granulocyte biomarkers are “even with” those of referring ELISA tests, he added. Furthermore, the evaluation of these biomarkers can be completed within hours, thus providing the potential for timely support for therapeutic decisions about patients with acute NMOSD.

It can be difficult to distinguish between NMOSD, MOGAD, and MS using a clinical examination and MRI scans alone. Assays for AQP4 and anti-MOG antibodies are the standard for refining the diagnosis, but obtaining the results of these assays takes 1-2 weeks. This time frame may delay the administration of urgently needed treatment.

Neutrophil granulocytes have various components that carry molecules that, although they are secreted to defend the host, also can damage tissue. These cells are common in brain tissue and CSF among patients with NMOSD. Patients with MOGAD often have neutrophil granulocytes as well, but the latter are rare in MS.
 

Biomarkers had high AUC

Dr. Leppert and colleagues conducted a study to evaluate whether these cells can distinguish NMOSD or MOGAD from MS. The investigators specifically examined the following neutrophil granule products: elastase, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8), and neutrophil gelatinase-associated lipocalin (NGAL). Dr. Leppert’s group evaluated CSF samples from 42 patients with NMOSD, 6 patients with MOGAD, and 41 patients with relapsing-remitting MS for these potential biomarkers. They also examined the samples for neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and S100B by conventional ELISA or single-molecule array assay. The investigators examined CSF samples from 25 healthy controls as a reference group.

Linear models allowed Dr. Leppert and colleagues to assess the association between biomarkers and disease groups. The investigators modeled the change of biomarker levels over time. They calculated receiver operating characteristic (ROC) curves and area under the curve (AUC) to estimate the potential to distinguish NMOSD and MOGAD from relapsing-remitting MS in acute disease phase (i.e., at 20 or fewer days after relapse), as well as between acute NMOSD and MOGAD. Finally, they assessed the association of biomarkers with Expanded Disability Status Scale (EDSS) score in acute NMOSD and relapsing-remitting MS using linear models and Spearman correlation.

Dr. Leppert and colleagues found that levels of NfL were increased among patients, compared with healthy controls. GFAP levels were increased in patients with NMOSD, compared with controls.

Among patients with NMOSD, all four neutrophil granulocyte markers were significantly increased, compared with healthy controls and patients with acute relapsing-remitting MS. Among patients with MOGAD, elastase, MPO, and MMP-8 were increased, compared with healthy controls and patients with acute relapsing-remitting MS. In ROC analyses comparing patients with acute NMOSD or MOGAD against those with acute RRMS, the AUC of elastase and NGAL was 0.91, the AUC of MPO was 0.82, and the AUC of MMP-8 was 0.81.

Levels of S100B were increased in 89% of patients with acute NMOSD (AUC = 0.82), and levels of GFAP were increased in 83% of patients with acute NMOSD (AUC = 0.80), compared with median values of MOGAD. Among patients with acute NMOSD, EDSS scores correlated with all four neutrophil granulocyte markers and GFAP, but not with NfL and S100B. The neutrophil granulocyte markers in acute NMOSD are likely drivers of tissue damage, said Dr. Leppert. “We may end up in the future with an algorithm that combines several markers into one score to optimize the differentiating power.” The next step will be to validate these findings in a larger sample set, he said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
 

Biomarkers may predict attacks

Granulocyte markers may provide support for a diagnosis of NMOSD over MS even in the small subgroup of patients who are seronegative for AQP4-IgG and MOG-IgG, said Brian G. Weinshenker, MD, a neurology consultant at Mayo Clinic in Rochester, Minn. In the study by Leppert and colleagues, granulocyte markers did not appear able to distinguish patients with AQP4-IgG–associated NMOSD from those with MOG-IgG–associated NMOSD, although astrocyte markers did in previous studies. “Granulocyte markers are primarily effective when studied in the context of an acute attack, unlike the antibody biomarkers,” said Dr. Weinshenker.

“Perhaps the most promising aspect of these new biomarkers is the fact that they are biomarkers for important mediators of tissue toxicity and seemed to correlate with attack-related disability,” he added. “They may prove to be prognostic indicators of attacks, and might influence the aggressiveness of acute management of attacks, although, in practice, all patients with NMOSD attacks, especially those associated with AQP4-IgG, should be managed aggressively.”

The current results will need independent confirmation before these biomarkers can be integrated into clinical practice, said Dr. Weinshenker. Studies should include patients with other diseases that can cause inflammation in the spinal cord and optic nerve (e.g., acute disseminated encephalomyelitis, infectious myelitis, and parainfectious myelitis) as relevant controls to determine whether granulocyte markers can distinguish these conditions effectively.

In addition, patients with discrepant values for elevations of granulocyte markers and serological indicators of NMOSD should be followed to determine the markers’ significance in this population, as well as to understand the value that measuring neutrophil markers provides. “Further studies of how these markers might herald attacks and predict disability might render these tests useful in monitoring patients and potentially intervening early in the attack process before attacks are fully manifest clinically.”

Dr. Leppert did not report any disclosures or any outside funding for the study. Dr. Weinshenker receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen for a patent on NMO-IgG as a diagnostic test for NMOSD. He has served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for NMOSD.

[email protected]

SOURCE: Leppert D et al. MSVirtual2020. Abstract LB01.03.

Neutrophil granulocyte biomarkers can distinguish between neuromyelitis optica spectrum disorders (NMOSD) and anti-MOG antibody–associated disease (MOGAD) on one hand and multiple sclerosis (MS) on the other hand, researchers reported. If current findings are replicated, these biomarkers will help neurologists distinguish between these disorders in the future, even in cases that are negative for autoantibodies, they said.

The sensitivity and specificity profile of neutrophil granulocyte biomarkers is not as good as that for cell-based assays for AQP4 and anti-MOG antibodies when it comes to distinguishing between acute NMOSD or MOGAD versus acute relapsing-remitting MS, said David Leppert, MD, of University Hospital Basel (Switzerland) and the University of Basel. But the sensitivity and specificity of neutrophil granulocyte biomarkers are “even with” those of referring ELISA tests, he added. Furthermore, the evaluation of these biomarkers can be completed within hours, thus providing the potential for timely support for therapeutic decisions about patients with acute NMOSD.

It can be difficult to distinguish between NMOSD, MOGAD, and MS using a clinical examination and MRI scans alone. Assays for AQP4 and anti-MOG antibodies are the standard for refining the diagnosis, but obtaining the results of these assays takes 1-2 weeks. This time frame may delay the administration of urgently needed treatment.

Neutrophil granulocytes have various components that carry molecules that, although they are secreted to defend the host, also can damage tissue. These cells are common in brain tissue and CSF among patients with NMOSD. Patients with MOGAD often have neutrophil granulocytes as well, but the latter are rare in MS.
 

Biomarkers had high AUC

Dr. Leppert and colleagues conducted a study to evaluate whether these cells can distinguish NMOSD or MOGAD from MS. The investigators specifically examined the following neutrophil granule products: elastase, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8), and neutrophil gelatinase-associated lipocalin (NGAL). Dr. Leppert’s group evaluated CSF samples from 42 patients with NMOSD, 6 patients with MOGAD, and 41 patients with relapsing-remitting MS for these potential biomarkers. They also examined the samples for neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and S100B by conventional ELISA or single-molecule array assay. The investigators examined CSF samples from 25 healthy controls as a reference group.

Linear models allowed Dr. Leppert and colleagues to assess the association between biomarkers and disease groups. The investigators modeled the change of biomarker levels over time. They calculated receiver operating characteristic (ROC) curves and area under the curve (AUC) to estimate the potential to distinguish NMOSD and MOGAD from relapsing-remitting MS in acute disease phase (i.e., at 20 or fewer days after relapse), as well as between acute NMOSD and MOGAD. Finally, they assessed the association of biomarkers with Expanded Disability Status Scale (EDSS) score in acute NMOSD and relapsing-remitting MS using linear models and Spearman correlation.

Dr. Leppert and colleagues found that levels of NfL were increased among patients, compared with healthy controls. GFAP levels were increased in patients with NMOSD, compared with controls.

Among patients with NMOSD, all four neutrophil granulocyte markers were significantly increased, compared with healthy controls and patients with acute relapsing-remitting MS. Among patients with MOGAD, elastase, MPO, and MMP-8 were increased, compared with healthy controls and patients with acute relapsing-remitting MS. In ROC analyses comparing patients with acute NMOSD or MOGAD against those with acute RRMS, the AUC of elastase and NGAL was 0.91, the AUC of MPO was 0.82, and the AUC of MMP-8 was 0.81.

Levels of S100B were increased in 89% of patients with acute NMOSD (AUC = 0.82), and levels of GFAP were increased in 83% of patients with acute NMOSD (AUC = 0.80), compared with median values of MOGAD. Among patients with acute NMOSD, EDSS scores correlated with all four neutrophil granulocyte markers and GFAP, but not with NfL and S100B. The neutrophil granulocyte markers in acute NMOSD are likely drivers of tissue damage, said Dr. Leppert. “We may end up in the future with an algorithm that combines several markers into one score to optimize the differentiating power.” The next step will be to validate these findings in a larger sample set, he said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
 

Biomarkers may predict attacks

Granulocyte markers may provide support for a diagnosis of NMOSD over MS even in the small subgroup of patients who are seronegative for AQP4-IgG and MOG-IgG, said Brian G. Weinshenker, MD, a neurology consultant at Mayo Clinic in Rochester, Minn. In the study by Leppert and colleagues, granulocyte markers did not appear able to distinguish patients with AQP4-IgG–associated NMOSD from those with MOG-IgG–associated NMOSD, although astrocyte markers did in previous studies. “Granulocyte markers are primarily effective when studied in the context of an acute attack, unlike the antibody biomarkers,” said Dr. Weinshenker.

“Perhaps the most promising aspect of these new biomarkers is the fact that they are biomarkers for important mediators of tissue toxicity and seemed to correlate with attack-related disability,” he added. “They may prove to be prognostic indicators of attacks, and might influence the aggressiveness of acute management of attacks, although, in practice, all patients with NMOSD attacks, especially those associated with AQP4-IgG, should be managed aggressively.”

The current results will need independent confirmation before these biomarkers can be integrated into clinical practice, said Dr. Weinshenker. Studies should include patients with other diseases that can cause inflammation in the spinal cord and optic nerve (e.g., acute disseminated encephalomyelitis, infectious myelitis, and parainfectious myelitis) as relevant controls to determine whether granulocyte markers can distinguish these conditions effectively.

In addition, patients with discrepant values for elevations of granulocyte markers and serological indicators of NMOSD should be followed to determine the markers’ significance in this population, as well as to understand the value that measuring neutrophil markers provides. “Further studies of how these markers might herald attacks and predict disability might render these tests useful in monitoring patients and potentially intervening early in the attack process before attacks are fully manifest clinically.”

Dr. Leppert did not report any disclosures or any outside funding for the study. Dr. Weinshenker receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen for a patent on NMO-IgG as a diagnostic test for NMOSD. He has served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for NMOSD.

[email protected]

SOURCE: Leppert D et al. MSVirtual2020. Abstract LB01.03.

Neutrophil granulocyte biomarkers can distinguish between neuromyelitis optica spectrum disorders (NMOSD) and anti-MOG antibody–associated disease (MOGAD) on one hand and multiple sclerosis (MS) on the other hand, researchers reported. If current findings are replicated, these biomarkers will help neurologists distinguish between these disorders in the future, even in cases that are negative for autoantibodies, they said.

The sensitivity and specificity profile of neutrophil granulocyte biomarkers is not as good as that for cell-based assays for AQP4 and anti-MOG antibodies when it comes to distinguishing between acute NMOSD or MOGAD versus acute relapsing-remitting MS, said David Leppert, MD, of University Hospital Basel (Switzerland) and the University of Basel. But the sensitivity and specificity of neutrophil granulocyte biomarkers are “even with” those of referring ELISA tests, he added. Furthermore, the evaluation of these biomarkers can be completed within hours, thus providing the potential for timely support for therapeutic decisions about patients with acute NMOSD.

It can be difficult to distinguish between NMOSD, MOGAD, and MS using a clinical examination and MRI scans alone. Assays for AQP4 and anti-MOG antibodies are the standard for refining the diagnosis, but obtaining the results of these assays takes 1-2 weeks. This time frame may delay the administration of urgently needed treatment.

Neutrophil granulocytes have various components that carry molecules that, although they are secreted to defend the host, also can damage tissue. These cells are common in brain tissue and CSF among patients with NMOSD. Patients with MOGAD often have neutrophil granulocytes as well, but the latter are rare in MS.
 

Biomarkers had high AUC

Dr. Leppert and colleagues conducted a study to evaluate whether these cells can distinguish NMOSD or MOGAD from MS. The investigators specifically examined the following neutrophil granule products: elastase, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8), and neutrophil gelatinase-associated lipocalin (NGAL). Dr. Leppert’s group evaluated CSF samples from 42 patients with NMOSD, 6 patients with MOGAD, and 41 patients with relapsing-remitting MS for these potential biomarkers. They also examined the samples for neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and S100B by conventional ELISA or single-molecule array assay. The investigators examined CSF samples from 25 healthy controls as a reference group.

Linear models allowed Dr. Leppert and colleagues to assess the association between biomarkers and disease groups. The investigators modeled the change of biomarker levels over time. They calculated receiver operating characteristic (ROC) curves and area under the curve (AUC) to estimate the potential to distinguish NMOSD and MOGAD from relapsing-remitting MS in acute disease phase (i.e., at 20 or fewer days after relapse), as well as between acute NMOSD and MOGAD. Finally, they assessed the association of biomarkers with Expanded Disability Status Scale (EDSS) score in acute NMOSD and relapsing-remitting MS using linear models and Spearman correlation.

Dr. Leppert and colleagues found that levels of NfL were increased among patients, compared with healthy controls. GFAP levels were increased in patients with NMOSD, compared with controls.

Among patients with NMOSD, all four neutrophil granulocyte markers were significantly increased, compared with healthy controls and patients with acute relapsing-remitting MS. Among patients with MOGAD, elastase, MPO, and MMP-8 were increased, compared with healthy controls and patients with acute relapsing-remitting MS. In ROC analyses comparing patients with acute NMOSD or MOGAD against those with acute RRMS, the AUC of elastase and NGAL was 0.91, the AUC of MPO was 0.82, and the AUC of MMP-8 was 0.81.

Levels of S100B were increased in 89% of patients with acute NMOSD (AUC = 0.82), and levels of GFAP were increased in 83% of patients with acute NMOSD (AUC = 0.80), compared with median values of MOGAD. Among patients with acute NMOSD, EDSS scores correlated with all four neutrophil granulocyte markers and GFAP, but not with NfL and S100B. The neutrophil granulocyte markers in acute NMOSD are likely drivers of tissue damage, said Dr. Leppert. “We may end up in the future with an algorithm that combines several markers into one score to optimize the differentiating power.” The next step will be to validate these findings in a larger sample set, he said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.
 

Biomarkers may predict attacks

Granulocyte markers may provide support for a diagnosis of NMOSD over MS even in the small subgroup of patients who are seronegative for AQP4-IgG and MOG-IgG, said Brian G. Weinshenker, MD, a neurology consultant at Mayo Clinic in Rochester, Minn. In the study by Leppert and colleagues, granulocyte markers did not appear able to distinguish patients with AQP4-IgG–associated NMOSD from those with MOG-IgG–associated NMOSD, although astrocyte markers did in previous studies. “Granulocyte markers are primarily effective when studied in the context of an acute attack, unlike the antibody biomarkers,” said Dr. Weinshenker.

“Perhaps the most promising aspect of these new biomarkers is the fact that they are biomarkers for important mediators of tissue toxicity and seemed to correlate with attack-related disability,” he added. “They may prove to be prognostic indicators of attacks, and might influence the aggressiveness of acute management of attacks, although, in practice, all patients with NMOSD attacks, especially those associated with AQP4-IgG, should be managed aggressively.”

The current results will need independent confirmation before these biomarkers can be integrated into clinical practice, said Dr. Weinshenker. Studies should include patients with other diseases that can cause inflammation in the spinal cord and optic nerve (e.g., acute disseminated encephalomyelitis, infectious myelitis, and parainfectious myelitis) as relevant controls to determine whether granulocyte markers can distinguish these conditions effectively.

In addition, patients with discrepant values for elevations of granulocyte markers and serological indicators of NMOSD should be followed to determine the markers’ significance in this population, as well as to understand the value that measuring neutrophil markers provides. “Further studies of how these markers might herald attacks and predict disability might render these tests useful in monitoring patients and potentially intervening early in the attack process before attacks are fully manifest clinically.”

Dr. Leppert did not report any disclosures or any outside funding for the study. Dr. Weinshenker receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen for a patent on NMO-IgG as a diagnostic test for NMOSD. He has served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for NMOSD.

[email protected]

SOURCE: Leppert D et al. MSVirtual2020. Abstract LB01.03.

In patients with tuberous sclerosis complex (TSC), preventive treatment with vigabatrin is safe and changes the natural history of seizures, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. This treatment strategy reduces the risk and severity of epilepsy, said the investigators.

As much as 90% of patients with TSC have epilepsy. Seizures generally start during infancy and are often resistant to medication. Clinicians are increasingly able to diagnose TSC prenatally, thus creating an opportunity for pursuing preventive strategies.

In the multicenter EPISTOP trial, Katarzyna Kotulska, MD, head of neurology and epileptology at Children’s Memorial Health Institute in Warsaw, and colleagues compared the efficacy and safety of preventive vigabatrin treatment with those of conventional vigabatrin treatment in infants with TSC. The researchers followed 94 infants with TSC and without a history of seizures with monthly video EEG. Conventional treatment was initiated after the first electrographic or clinical seizure, and preventive treatment was administered when epileptiform discharges were visible on EEG but before the first seizure.

Six sites randomly assigned patients to treatment in a equal groups in a randomized, controlled trial. At four other sites, treatment allocation was fixed in an open-label trial. All patients were followed until age 2 years. The study’s primary endpoint was the time to first clinical seizure.

A total of 53 patients participated in the randomized, controlled trial, and 41 participated in the open-label study; 79 patients completed the study. Of this group, 25 received preventive treatment, 25 received conventional treatment, and 22 patients had seizures before epileptiform activity was detected on EEG. Seven patients had neither seizures nor abnormal EEG.

The time to first clinical seizure was significantly longer in patients who received preventive treatment, compared with those who received conventional treatment. In the randomized, controlled trial, time to first seizure was 364 days in the preventive treatment group and 124 days in the conventional treatment group. In the open-label trial, time to first seizure was 426 days in the preventive treatment group and 106 days in the conventional treatment group.

A pooled analysis indicated that, at 24 months, preventive treatment significantly reduced the risk of clinical seizures (odds ratio, 0.21), drug-resistant epilepsy (OR, 0.23), and infantile spasms (OR, 0). The investigators did not record any adverse events related to preventive treatment.

The study was funded by the 7th Framework Program of the European Union. Dr. Kotulska did not report any disclosures.

[email protected]

SOURCE: Kotulska K et al. CNS-ICNA 2020, Abstract PL13.

In patients with tuberous sclerosis complex (TSC), preventive treatment with vigabatrin is safe and changes the natural history of seizures, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. This treatment strategy reduces the risk and severity of epilepsy, said the investigators.

As much as 90% of patients with TSC have epilepsy. Seizures generally start during infancy and are often resistant to medication. Clinicians are increasingly able to diagnose TSC prenatally, thus creating an opportunity for pursuing preventive strategies.

In the multicenter EPISTOP trial, Katarzyna Kotulska, MD, head of neurology and epileptology at Children’s Memorial Health Institute in Warsaw, and colleagues compared the efficacy and safety of preventive vigabatrin treatment with those of conventional vigabatrin treatment in infants with TSC. The researchers followed 94 infants with TSC and without a history of seizures with monthly video EEG. Conventional treatment was initiated after the first electrographic or clinical seizure, and preventive treatment was administered when epileptiform discharges were visible on EEG but before the first seizure.

Six sites randomly assigned patients to treatment in a equal groups in a randomized, controlled trial. At four other sites, treatment allocation was fixed in an open-label trial. All patients were followed until age 2 years. The study’s primary endpoint was the time to first clinical seizure.

A total of 53 patients participated in the randomized, controlled trial, and 41 participated in the open-label study; 79 patients completed the study. Of this group, 25 received preventive treatment, 25 received conventional treatment, and 22 patients had seizures before epileptiform activity was detected on EEG. Seven patients had neither seizures nor abnormal EEG.

The time to first clinical seizure was significantly longer in patients who received preventive treatment, compared with those who received conventional treatment. In the randomized, controlled trial, time to first seizure was 364 days in the preventive treatment group and 124 days in the conventional treatment group. In the open-label trial, time to first seizure was 426 days in the preventive treatment group and 106 days in the conventional treatment group.

A pooled analysis indicated that, at 24 months, preventive treatment significantly reduced the risk of clinical seizures (odds ratio, 0.21), drug-resistant epilepsy (OR, 0.23), and infantile spasms (OR, 0). The investigators did not record any adverse events related to preventive treatment.

The study was funded by the 7th Framework Program of the European Union. Dr. Kotulska did not report any disclosures.

[email protected]

SOURCE: Kotulska K et al. CNS-ICNA 2020, Abstract PL13.

In patients with tuberous sclerosis complex (TSC), preventive treatment with vigabatrin is safe and changes the natural history of seizures, according to research presented at the 2020 CNS-ICNA Conjoint Meeting, held virtually this year. This treatment strategy reduces the risk and severity of epilepsy, said the investigators.

As much as 90% of patients with TSC have epilepsy. Seizures generally start during infancy and are often resistant to medication. Clinicians are increasingly able to diagnose TSC prenatally, thus creating an opportunity for pursuing preventive strategies.

In the multicenter EPISTOP trial, Katarzyna Kotulska, MD, head of neurology and epileptology at Children’s Memorial Health Institute in Warsaw, and colleagues compared the efficacy and safety of preventive vigabatrin treatment with those of conventional vigabatrin treatment in infants with TSC. The researchers followed 94 infants with TSC and without a history of seizures with monthly video EEG. Conventional treatment was initiated after the first electrographic or clinical seizure, and preventive treatment was administered when epileptiform discharges were visible on EEG but before the first seizure.

Six sites randomly assigned patients to treatment in a equal groups in a randomized, controlled trial. At four other sites, treatment allocation was fixed in an open-label trial. All patients were followed until age 2 years. The study’s primary endpoint was the time to first clinical seizure.

A total of 53 patients participated in the randomized, controlled trial, and 41 participated in the open-label study; 79 patients completed the study. Of this group, 25 received preventive treatment, 25 received conventional treatment, and 22 patients had seizures before epileptiform activity was detected on EEG. Seven patients had neither seizures nor abnormal EEG.

The time to first clinical seizure was significantly longer in patients who received preventive treatment, compared with those who received conventional treatment. In the randomized, controlled trial, time to first seizure was 364 days in the preventive treatment group and 124 days in the conventional treatment group. In the open-label trial, time to first seizure was 426 days in the preventive treatment group and 106 days in the conventional treatment group.

A pooled analysis indicated that, at 24 months, preventive treatment significantly reduced the risk of clinical seizures (odds ratio, 0.21), drug-resistant epilepsy (OR, 0.23), and infantile spasms (OR, 0). The investigators did not record any adverse events related to preventive treatment.

The study was funded by the 7th Framework Program of the European Union. Dr. Kotulska did not report any disclosures.

[email protected]

SOURCE: Kotulska K et al. CNS-ICNA 2020, Abstract PL13.