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Erik Greb joined the staff of Neurology Reviews in January 2012. Since then, he has attended scientific conferences, conducted video interviews, and written about clinical research in multiple sclerosis, epilepsy, Parkinson's disease, Alzheimer's disease, stroke, and other neurologic disorders. In addition to news articles, Erik has written investigative stories about multiple sclerosis, headache, and epilepsy. He previously wrote about pharmaceutical manufacturing, drug formulation and delivery, quality assurance, and regulation for Pharmaceutical Technology.
Black holes are associated with impaired cognition in MS
SEATTLE – according to an investigation presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Black holes are not associated with physical function, however. Evaluating black holes as part of routine clinical practice could be a quick method for screening people with MS for referral to a comprehensive cognitive assessment, said the authors.
Black holes (also known as T1-hypointense lesions) can be used as a marker of axonal loss and neuronal tissue destruction in patients with MS. Loss of axons and destruction of neuronal tissue contribute to cognitive and physical disability, but the literature contains few data about whether black holes correlate with cognitive and physical outcomes in MS.
Serkan Özakbas, MD, professor of neurology at Dokuz Eylül University in Izmir, Turkey, and colleagues examined 226 patients with MS to investigate this potential correlation. The population’s median Expanded Disability Status Scale score was 1.5. The researchers categorized participants into two groups according whether they had at least one black hole or not. They assessed patients’ cognitive function by administering the Brief International Cognitive Assessment for MS (BICAMS), which comprises the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test II (CVLT-II), and the Brief Visuospatial Memory Test–Revised (BVMTR). They evaluated participants’ physical function using the Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (9HPT), 6-Minute Walk Test (6MWT), Timed Up and Go (TUG), and 12-Item MS Walking Scale (MSWS-12).
In all, 116 (43.6%) participants had at least one black hole, and 150 (56.4%) had no black hole. Dr. Özakbas and colleagues found no significant difference between patients with and without black holes on the T25FW, 9HPT, 6MWT, TUG, MSWS-12, and CVLT-II. Patients without a black hole, however, had significantly higher SDMT (49.0 vs 42.9) and BVMTR (26.3 vs 23.3) scores, compared with those with at least one black hole.
“This study suggests that presence of black holes is related to cognitive function, but not to physical function,” the researchers concluded.
The investigators had no disclosures and conducted their study without financial support.
SOURCE: Özakbas S et al. CMSC 2019, Abstract IMG02.
SEATTLE – according to an investigation presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Black holes are not associated with physical function, however. Evaluating black holes as part of routine clinical practice could be a quick method for screening people with MS for referral to a comprehensive cognitive assessment, said the authors.
Black holes (also known as T1-hypointense lesions) can be used as a marker of axonal loss and neuronal tissue destruction in patients with MS. Loss of axons and destruction of neuronal tissue contribute to cognitive and physical disability, but the literature contains few data about whether black holes correlate with cognitive and physical outcomes in MS.
Serkan Özakbas, MD, professor of neurology at Dokuz Eylül University in Izmir, Turkey, and colleagues examined 226 patients with MS to investigate this potential correlation. The population’s median Expanded Disability Status Scale score was 1.5. The researchers categorized participants into two groups according whether they had at least one black hole or not. They assessed patients’ cognitive function by administering the Brief International Cognitive Assessment for MS (BICAMS), which comprises the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test II (CVLT-II), and the Brief Visuospatial Memory Test–Revised (BVMTR). They evaluated participants’ physical function using the Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (9HPT), 6-Minute Walk Test (6MWT), Timed Up and Go (TUG), and 12-Item MS Walking Scale (MSWS-12).
In all, 116 (43.6%) participants had at least one black hole, and 150 (56.4%) had no black hole. Dr. Özakbas and colleagues found no significant difference between patients with and without black holes on the T25FW, 9HPT, 6MWT, TUG, MSWS-12, and CVLT-II. Patients without a black hole, however, had significantly higher SDMT (49.0 vs 42.9) and BVMTR (26.3 vs 23.3) scores, compared with those with at least one black hole.
“This study suggests that presence of black holes is related to cognitive function, but not to physical function,” the researchers concluded.
The investigators had no disclosures and conducted their study without financial support.
SOURCE: Özakbas S et al. CMSC 2019, Abstract IMG02.
SEATTLE – according to an investigation presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Black holes are not associated with physical function, however. Evaluating black holes as part of routine clinical practice could be a quick method for screening people with MS for referral to a comprehensive cognitive assessment, said the authors.
Black holes (also known as T1-hypointense lesions) can be used as a marker of axonal loss and neuronal tissue destruction in patients with MS. Loss of axons and destruction of neuronal tissue contribute to cognitive and physical disability, but the literature contains few data about whether black holes correlate with cognitive and physical outcomes in MS.
Serkan Özakbas, MD, professor of neurology at Dokuz Eylül University in Izmir, Turkey, and colleagues examined 226 patients with MS to investigate this potential correlation. The population’s median Expanded Disability Status Scale score was 1.5. The researchers categorized participants into two groups according whether they had at least one black hole or not. They assessed patients’ cognitive function by administering the Brief International Cognitive Assessment for MS (BICAMS), which comprises the Symbol Digit Modalities Test (SDMT), California Verbal Learning Test II (CVLT-II), and the Brief Visuospatial Memory Test–Revised (BVMTR). They evaluated participants’ physical function using the Timed 25-Foot Walk (T25FW), Nine-Hole Peg Test (9HPT), 6-Minute Walk Test (6MWT), Timed Up and Go (TUG), and 12-Item MS Walking Scale (MSWS-12).
In all, 116 (43.6%) participants had at least one black hole, and 150 (56.4%) had no black hole. Dr. Özakbas and colleagues found no significant difference between patients with and without black holes on the T25FW, 9HPT, 6MWT, TUG, MSWS-12, and CVLT-II. Patients without a black hole, however, had significantly higher SDMT (49.0 vs 42.9) and BVMTR (26.3 vs 23.3) scores, compared with those with at least one black hole.
“This study suggests that presence of black holes is related to cognitive function, but not to physical function,” the researchers concluded.
The investigators had no disclosures and conducted their study without financial support.
SOURCE: Özakbas S et al. CMSC 2019, Abstract IMG02.
REPORTING FROM CMSC 2019
LAIV doesn’t up asthmatic children’s risk of lower respiratory events
, according to an analysis published in Vaccine.
The data corroborate other research indicating that live attenuated influenza vaccine (LAIV) is safe for children with asthma older than 2 years and suggest that the choice of vaccination in this population should be based on effectiveness, according to James D. Nordin, MD, MPH, a clinical researcher at HealthPartners Institute in Minneapolis, and colleagues.
Children and adolescents with asthma have an increased risk of morbidity if they contract influenza. They represent a disproportionate number of pediatric influenza hospitalizations and have been a focus of efforts to vaccinate children against influenza. Since 2003, the inactivated influenza vaccine (IIV) and the LAIV have been available. Research indicates that LAIV is more effective than IIV at preventing culture-confirmed influenza in children. Two studies found an increased risk of wheezing in children who received LAIV, but other studies failed to replicate these findings.
A retrospective cohort study
Dr. Nordin and associates conducted a retrospective observational cohort study to investigate whether use of a guideline recommending LAIV for children aged 2 years and older with asthma increased the risk of lower respiratory events within 21 or 42 days of vaccination, compared with standard guidelines to administer IIV in children with asthma. The investigators drew data from two large medical groups with independent clinical leadership that serve demographically similar populations in Minnesota. One group (the LAIV group) switched its preference for all children from IIV to LAIV in 2010. The control group continued using IIV for children with asthma throughout the study period. Each group operates more than 20 clinics.
The investigators included children and adolescents aged 2-17 years who presented during one or more influenza season from 2007-2008 through 2014-2015. Eligible participants had a diagnosis of asthma or wheezing, received one or more influenza vaccines, had continuous insurance enrollment, and had at least one primary care or asthma related subspecialty encounter. They excluded patients with contraindications for LAIV (e.g., pregnancy, malignancy, and cystic fibrosis) and those with any hospitalization, ED visit, or outpatient encounter for a lower respiratory event in the 42 days before influenza vaccination.
Dr. Nordin and colleagues used a generalized estimating equation regression to estimate the ratio of rate ratios (RORs) comparing events before and after vaccination between the LAIV guideline and control groups. The researchers examined covariates such as age, gender, race or ethnicity, Medicaid insurance for at least 1 month in the previous year, neighborhood poverty, and neighborhood rates of asthma.
No increased risk
The investigators included 4,771 children and 7,851 child-influenza records in their analysis. During the period from 2007 to 2010, there were 2,215 child-influenza records from children and adolescents included from the LAIV group and 735 from the IIV guideline group. From 2010 to 2015, there were 3,767 child-influenza records in children and adolescents from the LAIV group and 1,134 from the IIV guideline group. After the LAIV group adopted the new guideline, the proportion of patients receiving LAIV increased from 23% to 68% in the LAIV group and from 7% to 11% in the control group.
About 88% of lower respiratory events included diagnoses for asthma exacerbations. When the investigators adjusted the data for age, asthma severity, asthma control, race or ethnicity, and Medicaid coverage, they found no increase in lower respiratory events associated with the LAIV guideline. The adjusted ROR was 0.74 for lower respiratory events within 21 days of vaccination and 0.77 for lower respiratory events within 42 days of vaccination. The results were similar when Dr. Nordin and colleagues stratified the data by age group, and including additional covariates did not alter the ROR estimates. In all, 21 hospitalizations occurred within 42 days of influenza vaccination, and the LAIV guideline did not increase the risk for hospitalization.
“Findings from this study are consistent with several recent observational studies of LAIV in children and adolescents with asthma,” said Dr. Nordin and colleagues.
One limitation of the current study was that the data were restricted to the information available in electronic health care or claims records. The researchers therefore were able to observe only medically attended lower respiratory events. Furthermore, the exclusion of asthma management encounters and the classification of asthma severity were based on diagnoses, visits, and medication orders and fills. The estimates thus are prone to misclassification, which may have biased the results. Finally, information on important variables such as daycare attendance, presence of school-age siblings, and exposure to secondhand smoke was not available.
The research was funded by a grant from the National Institute of Allergy and Infectious Diseases. The authors had no relevant financial disclosures.
SOURCE: Nordin JD et al. Vaccine. 2019 Jun 10. doi: 10.1016/j.vaccine.2019.05.081.
, according to an analysis published in Vaccine.
The data corroborate other research indicating that live attenuated influenza vaccine (LAIV) is safe for children with asthma older than 2 years and suggest that the choice of vaccination in this population should be based on effectiveness, according to James D. Nordin, MD, MPH, a clinical researcher at HealthPartners Institute in Minneapolis, and colleagues.
Children and adolescents with asthma have an increased risk of morbidity if they contract influenza. They represent a disproportionate number of pediatric influenza hospitalizations and have been a focus of efforts to vaccinate children against influenza. Since 2003, the inactivated influenza vaccine (IIV) and the LAIV have been available. Research indicates that LAIV is more effective than IIV at preventing culture-confirmed influenza in children. Two studies found an increased risk of wheezing in children who received LAIV, but other studies failed to replicate these findings.
A retrospective cohort study
Dr. Nordin and associates conducted a retrospective observational cohort study to investigate whether use of a guideline recommending LAIV for children aged 2 years and older with asthma increased the risk of lower respiratory events within 21 or 42 days of vaccination, compared with standard guidelines to administer IIV in children with asthma. The investigators drew data from two large medical groups with independent clinical leadership that serve demographically similar populations in Minnesota. One group (the LAIV group) switched its preference for all children from IIV to LAIV in 2010. The control group continued using IIV for children with asthma throughout the study period. Each group operates more than 20 clinics.
The investigators included children and adolescents aged 2-17 years who presented during one or more influenza season from 2007-2008 through 2014-2015. Eligible participants had a diagnosis of asthma or wheezing, received one or more influenza vaccines, had continuous insurance enrollment, and had at least one primary care or asthma related subspecialty encounter. They excluded patients with contraindications for LAIV (e.g., pregnancy, malignancy, and cystic fibrosis) and those with any hospitalization, ED visit, or outpatient encounter for a lower respiratory event in the 42 days before influenza vaccination.
Dr. Nordin and colleagues used a generalized estimating equation regression to estimate the ratio of rate ratios (RORs) comparing events before and after vaccination between the LAIV guideline and control groups. The researchers examined covariates such as age, gender, race or ethnicity, Medicaid insurance for at least 1 month in the previous year, neighborhood poverty, and neighborhood rates of asthma.
No increased risk
The investigators included 4,771 children and 7,851 child-influenza records in their analysis. During the period from 2007 to 2010, there were 2,215 child-influenza records from children and adolescents included from the LAIV group and 735 from the IIV guideline group. From 2010 to 2015, there were 3,767 child-influenza records in children and adolescents from the LAIV group and 1,134 from the IIV guideline group. After the LAIV group adopted the new guideline, the proportion of patients receiving LAIV increased from 23% to 68% in the LAIV group and from 7% to 11% in the control group.
About 88% of lower respiratory events included diagnoses for asthma exacerbations. When the investigators adjusted the data for age, asthma severity, asthma control, race or ethnicity, and Medicaid coverage, they found no increase in lower respiratory events associated with the LAIV guideline. The adjusted ROR was 0.74 for lower respiratory events within 21 days of vaccination and 0.77 for lower respiratory events within 42 days of vaccination. The results were similar when Dr. Nordin and colleagues stratified the data by age group, and including additional covariates did not alter the ROR estimates. In all, 21 hospitalizations occurred within 42 days of influenza vaccination, and the LAIV guideline did not increase the risk for hospitalization.
“Findings from this study are consistent with several recent observational studies of LAIV in children and adolescents with asthma,” said Dr. Nordin and colleagues.
One limitation of the current study was that the data were restricted to the information available in electronic health care or claims records. The researchers therefore were able to observe only medically attended lower respiratory events. Furthermore, the exclusion of asthma management encounters and the classification of asthma severity were based on diagnoses, visits, and medication orders and fills. The estimates thus are prone to misclassification, which may have biased the results. Finally, information on important variables such as daycare attendance, presence of school-age siblings, and exposure to secondhand smoke was not available.
The research was funded by a grant from the National Institute of Allergy and Infectious Diseases. The authors had no relevant financial disclosures.
SOURCE: Nordin JD et al. Vaccine. 2019 Jun 10. doi: 10.1016/j.vaccine.2019.05.081.
, according to an analysis published in Vaccine.
The data corroborate other research indicating that live attenuated influenza vaccine (LAIV) is safe for children with asthma older than 2 years and suggest that the choice of vaccination in this population should be based on effectiveness, according to James D. Nordin, MD, MPH, a clinical researcher at HealthPartners Institute in Minneapolis, and colleagues.
Children and adolescents with asthma have an increased risk of morbidity if they contract influenza. They represent a disproportionate number of pediatric influenza hospitalizations and have been a focus of efforts to vaccinate children against influenza. Since 2003, the inactivated influenza vaccine (IIV) and the LAIV have been available. Research indicates that LAIV is more effective than IIV at preventing culture-confirmed influenza in children. Two studies found an increased risk of wheezing in children who received LAIV, but other studies failed to replicate these findings.
A retrospective cohort study
Dr. Nordin and associates conducted a retrospective observational cohort study to investigate whether use of a guideline recommending LAIV for children aged 2 years and older with asthma increased the risk of lower respiratory events within 21 or 42 days of vaccination, compared with standard guidelines to administer IIV in children with asthma. The investigators drew data from two large medical groups with independent clinical leadership that serve demographically similar populations in Minnesota. One group (the LAIV group) switched its preference for all children from IIV to LAIV in 2010. The control group continued using IIV for children with asthma throughout the study period. Each group operates more than 20 clinics.
The investigators included children and adolescents aged 2-17 years who presented during one or more influenza season from 2007-2008 through 2014-2015. Eligible participants had a diagnosis of asthma or wheezing, received one or more influenza vaccines, had continuous insurance enrollment, and had at least one primary care or asthma related subspecialty encounter. They excluded patients with contraindications for LAIV (e.g., pregnancy, malignancy, and cystic fibrosis) and those with any hospitalization, ED visit, or outpatient encounter for a lower respiratory event in the 42 days before influenza vaccination.
Dr. Nordin and colleagues used a generalized estimating equation regression to estimate the ratio of rate ratios (RORs) comparing events before and after vaccination between the LAIV guideline and control groups. The researchers examined covariates such as age, gender, race or ethnicity, Medicaid insurance for at least 1 month in the previous year, neighborhood poverty, and neighborhood rates of asthma.
No increased risk
The investigators included 4,771 children and 7,851 child-influenza records in their analysis. During the period from 2007 to 2010, there were 2,215 child-influenza records from children and adolescents included from the LAIV group and 735 from the IIV guideline group. From 2010 to 2015, there were 3,767 child-influenza records in children and adolescents from the LAIV group and 1,134 from the IIV guideline group. After the LAIV group adopted the new guideline, the proportion of patients receiving LAIV increased from 23% to 68% in the LAIV group and from 7% to 11% in the control group.
About 88% of lower respiratory events included diagnoses for asthma exacerbations. When the investigators adjusted the data for age, asthma severity, asthma control, race or ethnicity, and Medicaid coverage, they found no increase in lower respiratory events associated with the LAIV guideline. The adjusted ROR was 0.74 for lower respiratory events within 21 days of vaccination and 0.77 for lower respiratory events within 42 days of vaccination. The results were similar when Dr. Nordin and colleagues stratified the data by age group, and including additional covariates did not alter the ROR estimates. In all, 21 hospitalizations occurred within 42 days of influenza vaccination, and the LAIV guideline did not increase the risk for hospitalization.
“Findings from this study are consistent with several recent observational studies of LAIV in children and adolescents with asthma,” said Dr. Nordin and colleagues.
One limitation of the current study was that the data were restricted to the information available in electronic health care or claims records. The researchers therefore were able to observe only medically attended lower respiratory events. Furthermore, the exclusion of asthma management encounters and the classification of asthma severity were based on diagnoses, visits, and medication orders and fills. The estimates thus are prone to misclassification, which may have biased the results. Finally, information on important variables such as daycare attendance, presence of school-age siblings, and exposure to secondhand smoke was not available.
The research was funded by a grant from the National Institute of Allergy and Infectious Diseases. The authors had no relevant financial disclosures.
SOURCE: Nordin JD et al. Vaccine. 2019 Jun 10. doi: 10.1016/j.vaccine.2019.05.081.
FROM VACCINE
Tranexamic acid may not improve neurologic outcomes in patients with TBI
PHILADELPHIA – according to an investigation presented at the annual meeting of the American Academy of Neurology. For patients with TBI and intracranial hemorrhage (ICH), however, treatment with a 2-gram bolus of tranexamic acid within 42 minutes of injury significantly improves the rate of 28-day survival. Tranexamic acid therefore “is the first therapeutic with evidence for benefit in acute TBI,” said Susan Rowell, MD, trauma medical director at Duke University in Durham, North Carolina.
No effective treatment is available for TBI, which is a major cause of death after trauma. In 2010, the CRASH-2 trial (Lancet. 2010 Jul 03;376[9734]:23-32), suggested that tranexamic acid, a lysine analogue that decreases the breakdown of clots, safely reduced the rate of death from hemorrhage in patients with trauma and bleeding. Patients treated within 1 hour of injury were significantly more likely to survive than those treated at 1 hour or more after injury.
Two small, prospective trials failed to show that tranexamic acid reduced in-hospital mortality, improved neurologic function at discharge, or reduced the progression of ICH. A meta-analysis of both trials, however, showed a trend toward a benefit of treatment with this therapy.
A multicenter, prehospital trial
Dr. Rowell and colleagues hypothesized that prehospital administration of tranexamic acid to patients with moderate to severe TBI early after injury would increase the likelihood of a favorable neurologic outcome. Between March 2015 and March 2017, they enrolled 1,280 participants in a multicenter, prehospital trial. Eligible participants had moderate to severe TBI, were not in shock (as evidenced by a systolic blood pressure greater than 90 mm Hg before randomization), and were enrolled within 2 hours of injury.
Patients were randomized to one of three treatment arms and followed for 6 months. The first treatment arm received a 1-gram bolus of tranexamic acid before hospital admission and an 8-hour, 1-gram infusion of tranexamic acid in the hospital. The second arm received a 2-gram bolus of tranexamic acid before hospital admission and a placebo infusion in the hospital. The third arm received a placebo bolus and placebo infusion. Paramedics and participants were blinded to treatment assignment. The trial was conducted at 20 hospitals and 39 emergency medical services agencies in the United States and Canada.
The study’s primary outcome was functional neurologic outcome at 6 months, as measured by the Glasgow Outcomes Scale – Extended (GOSE). The investigators dichotomized results into favorable and poor categories. Other prespecified outcomes included early and late mortality, the disability rating scale (DRS), and progression of ICH.
Treatment was administered early
The researchers identified 1,280 eligible patients, of whom 1,063 were randomized. The modified intention-to-treat analysis included 309 participants in the placebo group, 312 in the bolus-maintenance group (the 1-gram group), and 345 in the bolus-only group (the 2-gram group). The population’s average age was approximately 42 years, and 75% of the sample was male. About half of the patients had a Glasgow Coma Scale score between 3 and 8. Injury severity and prehospital care were similar among the groups.
The researchers provided the drug infusion at an average of 0.7 hours (42 minutes) after injury, “which is actually quite early,” said Dr. Rowell. They observed few infusion-related deviations, and the entire bolus was infused in about 95% of patients. Approximately 70% of patients received the full 8-hour infusion. This result was influenced partly by stopping rules and by providers who requested unblinding to give open-label tranexamic acid. Overall, 57% of patients in the trial had an ICH on head CT, which was approximately the proportion that the researchers had anticipated.
Dr. Rowell and colleagues completed the 6-month follow-up for 85% of patients. They saw no difference in the 6-month neurologic outcome between the group of all patients who received tranexamic acid and those who received placebo. The investigators also saw no differences between groups in early and late mortality and the DRS.
About half of patients with ICH were evaluated for progression. Progression occurred in 20% of the placebo arm, 17% of the bolus-maintenance arm, and 15% of the bolus-only arm. The differences between groups were not statistically significant. Participants in the bolus-only group, however, were significantly less likely to die, compared with the placebo and the bolus-maintenance groups. The odds ratio of death for the bolus-only group, compared with the others, was about 0.5. The absolute mortality rate for the placebo and bolus-maintenance groups was 17%, compared with 12% for the bolus-only group. Most deaths were attributable to TBI, and few patients died of exsanguination.
In addition, the bolus-only group also had improved long-term neurologic outcome, as assessed by the 6-month DRS and the 6-month GOSE, compared with the bolus maintenance group.
Among patients with ICH, survival increased by approximately 12% at 10 hours after injury in the bolus-only group, compared with the bolus-maintenance and placebo groups. This difference persisted throughout the follow-up period, said Dr. Rowell.
Among predefined major adverse events, seizure-like activity occurred in 5% of the bolus-only group, compared with 2% of the placebo and bolus-maintenance groups. The researchers found no significant differences in any thrombotic event between the bolus-only group and the placebo group.
The study was sponsored by University of Washington, Seattle. Collaborators included the National Heart, Lung, and Blood Institute; the U.S. Army Medical Research and Development Command; and the American Heart Association. Dr. Rowell had no relevant disclosures.
SOURCE: Rowell S et al. AAN 2019, Abstract.
PHILADELPHIA – according to an investigation presented at the annual meeting of the American Academy of Neurology. For patients with TBI and intracranial hemorrhage (ICH), however, treatment with a 2-gram bolus of tranexamic acid within 42 minutes of injury significantly improves the rate of 28-day survival. Tranexamic acid therefore “is the first therapeutic with evidence for benefit in acute TBI,” said Susan Rowell, MD, trauma medical director at Duke University in Durham, North Carolina.
No effective treatment is available for TBI, which is a major cause of death after trauma. In 2010, the CRASH-2 trial (Lancet. 2010 Jul 03;376[9734]:23-32), suggested that tranexamic acid, a lysine analogue that decreases the breakdown of clots, safely reduced the rate of death from hemorrhage in patients with trauma and bleeding. Patients treated within 1 hour of injury were significantly more likely to survive than those treated at 1 hour or more after injury.
Two small, prospective trials failed to show that tranexamic acid reduced in-hospital mortality, improved neurologic function at discharge, or reduced the progression of ICH. A meta-analysis of both trials, however, showed a trend toward a benefit of treatment with this therapy.
A multicenter, prehospital trial
Dr. Rowell and colleagues hypothesized that prehospital administration of tranexamic acid to patients with moderate to severe TBI early after injury would increase the likelihood of a favorable neurologic outcome. Between March 2015 and March 2017, they enrolled 1,280 participants in a multicenter, prehospital trial. Eligible participants had moderate to severe TBI, were not in shock (as evidenced by a systolic blood pressure greater than 90 mm Hg before randomization), and were enrolled within 2 hours of injury.
Patients were randomized to one of three treatment arms and followed for 6 months. The first treatment arm received a 1-gram bolus of tranexamic acid before hospital admission and an 8-hour, 1-gram infusion of tranexamic acid in the hospital. The second arm received a 2-gram bolus of tranexamic acid before hospital admission and a placebo infusion in the hospital. The third arm received a placebo bolus and placebo infusion. Paramedics and participants were blinded to treatment assignment. The trial was conducted at 20 hospitals and 39 emergency medical services agencies in the United States and Canada.
The study’s primary outcome was functional neurologic outcome at 6 months, as measured by the Glasgow Outcomes Scale – Extended (GOSE). The investigators dichotomized results into favorable and poor categories. Other prespecified outcomes included early and late mortality, the disability rating scale (DRS), and progression of ICH.
Treatment was administered early
The researchers identified 1,280 eligible patients, of whom 1,063 were randomized. The modified intention-to-treat analysis included 309 participants in the placebo group, 312 in the bolus-maintenance group (the 1-gram group), and 345 in the bolus-only group (the 2-gram group). The population’s average age was approximately 42 years, and 75% of the sample was male. About half of the patients had a Glasgow Coma Scale score between 3 and 8. Injury severity and prehospital care were similar among the groups.
The researchers provided the drug infusion at an average of 0.7 hours (42 minutes) after injury, “which is actually quite early,” said Dr. Rowell. They observed few infusion-related deviations, and the entire bolus was infused in about 95% of patients. Approximately 70% of patients received the full 8-hour infusion. This result was influenced partly by stopping rules and by providers who requested unblinding to give open-label tranexamic acid. Overall, 57% of patients in the trial had an ICH on head CT, which was approximately the proportion that the researchers had anticipated.
Dr. Rowell and colleagues completed the 6-month follow-up for 85% of patients. They saw no difference in the 6-month neurologic outcome between the group of all patients who received tranexamic acid and those who received placebo. The investigators also saw no differences between groups in early and late mortality and the DRS.
About half of patients with ICH were evaluated for progression. Progression occurred in 20% of the placebo arm, 17% of the bolus-maintenance arm, and 15% of the bolus-only arm. The differences between groups were not statistically significant. Participants in the bolus-only group, however, were significantly less likely to die, compared with the placebo and the bolus-maintenance groups. The odds ratio of death for the bolus-only group, compared with the others, was about 0.5. The absolute mortality rate for the placebo and bolus-maintenance groups was 17%, compared with 12% for the bolus-only group. Most deaths were attributable to TBI, and few patients died of exsanguination.
In addition, the bolus-only group also had improved long-term neurologic outcome, as assessed by the 6-month DRS and the 6-month GOSE, compared with the bolus maintenance group.
Among patients with ICH, survival increased by approximately 12% at 10 hours after injury in the bolus-only group, compared with the bolus-maintenance and placebo groups. This difference persisted throughout the follow-up period, said Dr. Rowell.
Among predefined major adverse events, seizure-like activity occurred in 5% of the bolus-only group, compared with 2% of the placebo and bolus-maintenance groups. The researchers found no significant differences in any thrombotic event between the bolus-only group and the placebo group.
The study was sponsored by University of Washington, Seattle. Collaborators included the National Heart, Lung, and Blood Institute; the U.S. Army Medical Research and Development Command; and the American Heart Association. Dr. Rowell had no relevant disclosures.
SOURCE: Rowell S et al. AAN 2019, Abstract.
PHILADELPHIA – according to an investigation presented at the annual meeting of the American Academy of Neurology. For patients with TBI and intracranial hemorrhage (ICH), however, treatment with a 2-gram bolus of tranexamic acid within 42 minutes of injury significantly improves the rate of 28-day survival. Tranexamic acid therefore “is the first therapeutic with evidence for benefit in acute TBI,” said Susan Rowell, MD, trauma medical director at Duke University in Durham, North Carolina.
No effective treatment is available for TBI, which is a major cause of death after trauma. In 2010, the CRASH-2 trial (Lancet. 2010 Jul 03;376[9734]:23-32), suggested that tranexamic acid, a lysine analogue that decreases the breakdown of clots, safely reduced the rate of death from hemorrhage in patients with trauma and bleeding. Patients treated within 1 hour of injury were significantly more likely to survive than those treated at 1 hour or more after injury.
Two small, prospective trials failed to show that tranexamic acid reduced in-hospital mortality, improved neurologic function at discharge, or reduced the progression of ICH. A meta-analysis of both trials, however, showed a trend toward a benefit of treatment with this therapy.
A multicenter, prehospital trial
Dr. Rowell and colleagues hypothesized that prehospital administration of tranexamic acid to patients with moderate to severe TBI early after injury would increase the likelihood of a favorable neurologic outcome. Between March 2015 and March 2017, they enrolled 1,280 participants in a multicenter, prehospital trial. Eligible participants had moderate to severe TBI, were not in shock (as evidenced by a systolic blood pressure greater than 90 mm Hg before randomization), and were enrolled within 2 hours of injury.
Patients were randomized to one of three treatment arms and followed for 6 months. The first treatment arm received a 1-gram bolus of tranexamic acid before hospital admission and an 8-hour, 1-gram infusion of tranexamic acid in the hospital. The second arm received a 2-gram bolus of tranexamic acid before hospital admission and a placebo infusion in the hospital. The third arm received a placebo bolus and placebo infusion. Paramedics and participants were blinded to treatment assignment. The trial was conducted at 20 hospitals and 39 emergency medical services agencies in the United States and Canada.
The study’s primary outcome was functional neurologic outcome at 6 months, as measured by the Glasgow Outcomes Scale – Extended (GOSE). The investigators dichotomized results into favorable and poor categories. Other prespecified outcomes included early and late mortality, the disability rating scale (DRS), and progression of ICH.
Treatment was administered early
The researchers identified 1,280 eligible patients, of whom 1,063 were randomized. The modified intention-to-treat analysis included 309 participants in the placebo group, 312 in the bolus-maintenance group (the 1-gram group), and 345 in the bolus-only group (the 2-gram group). The population’s average age was approximately 42 years, and 75% of the sample was male. About half of the patients had a Glasgow Coma Scale score between 3 and 8. Injury severity and prehospital care were similar among the groups.
The researchers provided the drug infusion at an average of 0.7 hours (42 minutes) after injury, “which is actually quite early,” said Dr. Rowell. They observed few infusion-related deviations, and the entire bolus was infused in about 95% of patients. Approximately 70% of patients received the full 8-hour infusion. This result was influenced partly by stopping rules and by providers who requested unblinding to give open-label tranexamic acid. Overall, 57% of patients in the trial had an ICH on head CT, which was approximately the proportion that the researchers had anticipated.
Dr. Rowell and colleagues completed the 6-month follow-up for 85% of patients. They saw no difference in the 6-month neurologic outcome between the group of all patients who received tranexamic acid and those who received placebo. The investigators also saw no differences between groups in early and late mortality and the DRS.
About half of patients with ICH were evaluated for progression. Progression occurred in 20% of the placebo arm, 17% of the bolus-maintenance arm, and 15% of the bolus-only arm. The differences between groups were not statistically significant. Participants in the bolus-only group, however, were significantly less likely to die, compared with the placebo and the bolus-maintenance groups. The odds ratio of death for the bolus-only group, compared with the others, was about 0.5. The absolute mortality rate for the placebo and bolus-maintenance groups was 17%, compared with 12% for the bolus-only group. Most deaths were attributable to TBI, and few patients died of exsanguination.
In addition, the bolus-only group also had improved long-term neurologic outcome, as assessed by the 6-month DRS and the 6-month GOSE, compared with the bolus maintenance group.
Among patients with ICH, survival increased by approximately 12% at 10 hours after injury in the bolus-only group, compared with the bolus-maintenance and placebo groups. This difference persisted throughout the follow-up period, said Dr. Rowell.
Among predefined major adverse events, seizure-like activity occurred in 5% of the bolus-only group, compared with 2% of the placebo and bolus-maintenance groups. The researchers found no significant differences in any thrombotic event between the bolus-only group and the placebo group.
The study was sponsored by University of Washington, Seattle. Collaborators included the National Heart, Lung, and Blood Institute; the U.S. Army Medical Research and Development Command; and the American Heart Association. Dr. Rowell had no relevant disclosures.
SOURCE: Rowell S et al. AAN 2019, Abstract.
REPORTING FROM AAN 2019
Key clinical point: Early administration of tranexamic acid after TBI does not improve neurologic outcome at 6 months.
Major finding: Patients with TBI and ICH who received a 2-g bolus of tranexamic acid had a 50% lower rate of mortality.
Study details: A multicenter, prehospital trial that enrolled 1,063 patients with moderate to severe TBI.
Disclosures: The study was sponsored by University of Washington, Seattle. Collaborators included the National Heart, Lung, and Blood Institute; the U.S. Army Medical Research and Development Command; and the American Heart Association. Dr. Rowell had no relevant disclosures.
Source: Rowell S et al. AAN 2019, Abstract.
Functional GI disorders are common in MS
SEATTLE – according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Managing patients’ psychiatric comorbidities could effectively reduce the burden of functional GI disorders, the researchers said.
Knowledge about the prevalence of functional GI disorders in the population of patients with MS is limited. For the most part, previous studies in this population have focused on irritable bowel syndrome (IBS). A 2013 study by Levinthal et al. (Mult Scler Int. 2013. doi: 10.1155/2013/319201) investigated the prevalence of other functional GI disorders in MS, but the literature contains little information about the clinical and demographic characteristics associated with these disorders. In addition, the extent to which comorbid functional GI disorders influence health-related quality of life in MS is also unknown.
Ruth Ann Marrie, MD, PhD, professor of neurology at the University of Manitoba in Winnipeg, and colleagues sought to determine the prevalence of functional bowel disorders, the demographic and clinical characteristics associated with functional bowel disorders, and the effects of these disorders on health-related quality of life in a large, diverse population of persons with MS. In 2014, the investigators used the Rome III questionnaire to survey participants in the North American Research Committee on MS (NARCOMS) registry about functional bowel disorders. Participants also provided information about their sociodemographic characteristics, their disability status (using Patient-Determined Disease Steps), and any comorbid depression or anxiety, their health behaviors, and their health-related quality of life (using the RAND-12).
Dr. Marrie and colleagues used these data to determine the prevalence of IBS, functional bloating, functional constipation, functional diarrhea, and functional dyspepsia. They used multivariable logistic regression models to examine the factors associated with any functional GI disorder, and they used linear regression to analyze the association between functional GI disorders and health-related quality of life using linear regression.
Dr. Marrie and colleagues identified 6,312 eligible respondents. Approximately 77% of the population was female, and the sample’s mean age was 58.3 years. In all, 2,647 respondents (42%) had a functional GI disorder. The most common was IBS, which affected 28.2% of participants. The prevalence of all functional GI disorders increased with increasing disability. Depression and anxiety were associated with increased odds of IBS and functional dyspepsia. After adjustment for sociodemographic and clinical characteristics, functional GI disorders were associated with lower physical and mental health-related quality of life.
The research was not supported by outside funding. Dr. Marrie had no disclosures, but other researchers had financial relationships with pharmaceutical companies, such as Merck, Novartis, Roche, Sanofi-Aventis, and Teva.
SOURCE: Marrie RA et al. CMSC 2019, Abstract QOL13.
SEATTLE – according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Managing patients’ psychiatric comorbidities could effectively reduce the burden of functional GI disorders, the researchers said.
Knowledge about the prevalence of functional GI disorders in the population of patients with MS is limited. For the most part, previous studies in this population have focused on irritable bowel syndrome (IBS). A 2013 study by Levinthal et al. (Mult Scler Int. 2013. doi: 10.1155/2013/319201) investigated the prevalence of other functional GI disorders in MS, but the literature contains little information about the clinical and demographic characteristics associated with these disorders. In addition, the extent to which comorbid functional GI disorders influence health-related quality of life in MS is also unknown.
Ruth Ann Marrie, MD, PhD, professor of neurology at the University of Manitoba in Winnipeg, and colleagues sought to determine the prevalence of functional bowel disorders, the demographic and clinical characteristics associated with functional bowel disorders, and the effects of these disorders on health-related quality of life in a large, diverse population of persons with MS. In 2014, the investigators used the Rome III questionnaire to survey participants in the North American Research Committee on MS (NARCOMS) registry about functional bowel disorders. Participants also provided information about their sociodemographic characteristics, their disability status (using Patient-Determined Disease Steps), and any comorbid depression or anxiety, their health behaviors, and their health-related quality of life (using the RAND-12).
Dr. Marrie and colleagues used these data to determine the prevalence of IBS, functional bloating, functional constipation, functional diarrhea, and functional dyspepsia. They used multivariable logistic regression models to examine the factors associated with any functional GI disorder, and they used linear regression to analyze the association between functional GI disorders and health-related quality of life using linear regression.
Dr. Marrie and colleagues identified 6,312 eligible respondents. Approximately 77% of the population was female, and the sample’s mean age was 58.3 years. In all, 2,647 respondents (42%) had a functional GI disorder. The most common was IBS, which affected 28.2% of participants. The prevalence of all functional GI disorders increased with increasing disability. Depression and anxiety were associated with increased odds of IBS and functional dyspepsia. After adjustment for sociodemographic and clinical characteristics, functional GI disorders were associated with lower physical and mental health-related quality of life.
The research was not supported by outside funding. Dr. Marrie had no disclosures, but other researchers had financial relationships with pharmaceutical companies, such as Merck, Novartis, Roche, Sanofi-Aventis, and Teva.
SOURCE: Marrie RA et al. CMSC 2019, Abstract QOL13.
SEATTLE – according to research presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. Managing patients’ psychiatric comorbidities could effectively reduce the burden of functional GI disorders, the researchers said.
Knowledge about the prevalence of functional GI disorders in the population of patients with MS is limited. For the most part, previous studies in this population have focused on irritable bowel syndrome (IBS). A 2013 study by Levinthal et al. (Mult Scler Int. 2013. doi: 10.1155/2013/319201) investigated the prevalence of other functional GI disorders in MS, but the literature contains little information about the clinical and demographic characteristics associated with these disorders. In addition, the extent to which comorbid functional GI disorders influence health-related quality of life in MS is also unknown.
Ruth Ann Marrie, MD, PhD, professor of neurology at the University of Manitoba in Winnipeg, and colleagues sought to determine the prevalence of functional bowel disorders, the demographic and clinical characteristics associated with functional bowel disorders, and the effects of these disorders on health-related quality of life in a large, diverse population of persons with MS. In 2014, the investigators used the Rome III questionnaire to survey participants in the North American Research Committee on MS (NARCOMS) registry about functional bowel disorders. Participants also provided information about their sociodemographic characteristics, their disability status (using Patient-Determined Disease Steps), and any comorbid depression or anxiety, their health behaviors, and their health-related quality of life (using the RAND-12).
Dr. Marrie and colleagues used these data to determine the prevalence of IBS, functional bloating, functional constipation, functional diarrhea, and functional dyspepsia. They used multivariable logistic regression models to examine the factors associated with any functional GI disorder, and they used linear regression to analyze the association between functional GI disorders and health-related quality of life using linear regression.
Dr. Marrie and colleagues identified 6,312 eligible respondents. Approximately 77% of the population was female, and the sample’s mean age was 58.3 years. In all, 2,647 respondents (42%) had a functional GI disorder. The most common was IBS, which affected 28.2% of participants. The prevalence of all functional GI disorders increased with increasing disability. Depression and anxiety were associated with increased odds of IBS and functional dyspepsia. After adjustment for sociodemographic and clinical characteristics, functional GI disorders were associated with lower physical and mental health-related quality of life.
The research was not supported by outside funding. Dr. Marrie had no disclosures, but other researchers had financial relationships with pharmaceutical companies, such as Merck, Novartis, Roche, Sanofi-Aventis, and Teva.
SOURCE: Marrie RA et al. CMSC 2019, Abstract QOL13.
REPORTING FROM CMSC 2019
Patients with focal epilepsy have progressive cortical thinning
, according to research published online July 1 in JAMA Neurology. Methods for preventing this thinning are unknown. “Our findings appear to highlight the need for longitudinal studies to develop disease-modifying treatments for epilepsy,” said Marian Galovic, MD, a doctoral student at University College London, and colleagues.
To date, neurologists have not found a definitive answer to the question of whether epilepsy is a static or progressive disease. Few longitudinal studies have examined patients with structural neuroimaging to determine whether the brain changes over time. The studies that have taken this approach have had small populations or have lacked control populations.
Comparing brain changes in patients and controls
Dr. Galovic and colleagues analyzed data for consecutive patients with focal epilepsy who underwent follow-up at the National Hospital for Neurology and Neurosurgery in London. The data were collected from Aug. 3, 2004, to Jan. 26, 2016. The researchers chose individuals who had at least 2 high-resolution T1-weighted MRI scans performed on the same scanner more than 6 months apart. They excluded patients with brain lesions other than hippocampal sclerosis, those with inadequate MRI scan quality, and those for whom clinical data were missing. To match these patients with controls, Dr. Galovic and colleagues chose three longitudinal data sets with data for healthy volunteers between ages 20 and 70 years. Each control participant had two high-resolution T1-weighted scans taken more than 6 months apart. The investigators matched patients and controls on age and sex. The automated and validated Computational Anatomy Toolbox (CAT12) estimated cortical thickness.
Dr. Galovic’s group included 190 patients with focal epilepsy, who had had 396 MRI scans, and 141 healthy controls, who had had 282 MRI scans, in their analysis. Age, sex, and image quality did not differ significantly between the two groups. Mean age was 36 years for patients and 35 years for controls. The proportion of women was 52.1% among patients and 53.9% among controls.
The rate of atrophy was doubled in patients
Approximately 77% of people with epilepsy had progressive cortical thinning that was distinct from that associated with normal aging. The mean overall annual rate of global cortical thinning was higher among patients with epilepsy (0.024) than among controls (0.011). The mean annual rate of cortical thinning increased among people with epilepsy who were older than 55 years. This rate was 0.021 in patients aged 18 to less than 35 years, compared with 0.023 in patients aged 35 to less than 55 years. Seizure frequency, number of antiepileptic drugs (AEDs) taken, and history of secondarily generalized seizures did not differ between age groups.
Compared with healthy controls, patients with focal epilepsy had widespread areas of greater progressive atrophy. Bilaterally affected areas included the lateral and posterior temporal lobes, posterior cingulate gyri, occipital lobes, pericentral gyri, and opercula. The distribution of progressive thinning in all patients with epilepsy was similar to regions connected to both hippocampi. Healthy controls had no areas of greater cortical thinning, compared with patients with epilepsy.
Progressive thinning in the left postcentral gyrus was greater in patients with left temporal lobe epilepsy (TLE) than in those with right TLE. Cortical thinning was more progressive in patients with right frontal lobe epilepsy (FLE) than in those with left FLE, particularly in right parietotemporal and right frontal areas.
Dr. Galovic and colleagues found no association between the rate of cortical thinning and seizure frequency, history of secondarily generalized seizures, or number of AEDs taken between MRIs. They found no difference in the rate of atrophy between patients with epilepsy with ongoing seizures and those without. The annual mean rate of cortical thinning was higher in people with a short duration of epilepsy (i.e., less than 5 years), compared with patients with a longer duration of epilepsy (i.e., 5 years or more).
A surrogate marker for neurodegeneration?
“The most likely cause of cortical thinning is neuronal loss, suggesting that these measurements are a surrogate marker for neurodegeneration,” said Dr. Galovic and colleagues. The finding that progressive morphologic changes were most pronounced in the first 5 years after epilepsy onset “supports the need for early diagnosis, rapid treatment, and reduction of delays of surgical referral in people with epilepsy,” they added.
One limitation of the current study is the fact that data from patients and controls were acquired using different MRI scanners. In addition, the patients included in the study had been referred to the center because their cases were more complicated, thus introducing the possibility of referral bias. The findings thus cannot be generalized readily to the overall population, said Dr. Galovic and colleagues.
Future studies should examine whether particular AEDs have differential influences on the progressive morphologic changes observed in epilepsy, said the investigators. “Future research should also address whether progressive changes in cortical morphologic characteristics correlate with deficits on serial cognitive testing or spreading of the irritative zone on EEG recordings,” they concluded.
The study and the authors received support from the Medical Research Council, the Wellcome Trust, and the University College London Hospital.
SOURCE: Galovic M et al. JAMA Neurol. 2019 Jul 1. doi: 10.1001/jamaneurol.2019.1708.
, according to research published online July 1 in JAMA Neurology. Methods for preventing this thinning are unknown. “Our findings appear to highlight the need for longitudinal studies to develop disease-modifying treatments for epilepsy,” said Marian Galovic, MD, a doctoral student at University College London, and colleagues.
To date, neurologists have not found a definitive answer to the question of whether epilepsy is a static or progressive disease. Few longitudinal studies have examined patients with structural neuroimaging to determine whether the brain changes over time. The studies that have taken this approach have had small populations or have lacked control populations.
Comparing brain changes in patients and controls
Dr. Galovic and colleagues analyzed data for consecutive patients with focal epilepsy who underwent follow-up at the National Hospital for Neurology and Neurosurgery in London. The data were collected from Aug. 3, 2004, to Jan. 26, 2016. The researchers chose individuals who had at least 2 high-resolution T1-weighted MRI scans performed on the same scanner more than 6 months apart. They excluded patients with brain lesions other than hippocampal sclerosis, those with inadequate MRI scan quality, and those for whom clinical data were missing. To match these patients with controls, Dr. Galovic and colleagues chose three longitudinal data sets with data for healthy volunteers between ages 20 and 70 years. Each control participant had two high-resolution T1-weighted scans taken more than 6 months apart. The investigators matched patients and controls on age and sex. The automated and validated Computational Anatomy Toolbox (CAT12) estimated cortical thickness.
Dr. Galovic’s group included 190 patients with focal epilepsy, who had had 396 MRI scans, and 141 healthy controls, who had had 282 MRI scans, in their analysis. Age, sex, and image quality did not differ significantly between the two groups. Mean age was 36 years for patients and 35 years for controls. The proportion of women was 52.1% among patients and 53.9% among controls.
The rate of atrophy was doubled in patients
Approximately 77% of people with epilepsy had progressive cortical thinning that was distinct from that associated with normal aging. The mean overall annual rate of global cortical thinning was higher among patients with epilepsy (0.024) than among controls (0.011). The mean annual rate of cortical thinning increased among people with epilepsy who were older than 55 years. This rate was 0.021 in patients aged 18 to less than 35 years, compared with 0.023 in patients aged 35 to less than 55 years. Seizure frequency, number of antiepileptic drugs (AEDs) taken, and history of secondarily generalized seizures did not differ between age groups.
Compared with healthy controls, patients with focal epilepsy had widespread areas of greater progressive atrophy. Bilaterally affected areas included the lateral and posterior temporal lobes, posterior cingulate gyri, occipital lobes, pericentral gyri, and opercula. The distribution of progressive thinning in all patients with epilepsy was similar to regions connected to both hippocampi. Healthy controls had no areas of greater cortical thinning, compared with patients with epilepsy.
Progressive thinning in the left postcentral gyrus was greater in patients with left temporal lobe epilepsy (TLE) than in those with right TLE. Cortical thinning was more progressive in patients with right frontal lobe epilepsy (FLE) than in those with left FLE, particularly in right parietotemporal and right frontal areas.
Dr. Galovic and colleagues found no association between the rate of cortical thinning and seizure frequency, history of secondarily generalized seizures, or number of AEDs taken between MRIs. They found no difference in the rate of atrophy between patients with epilepsy with ongoing seizures and those without. The annual mean rate of cortical thinning was higher in people with a short duration of epilepsy (i.e., less than 5 years), compared with patients with a longer duration of epilepsy (i.e., 5 years or more).
A surrogate marker for neurodegeneration?
“The most likely cause of cortical thinning is neuronal loss, suggesting that these measurements are a surrogate marker for neurodegeneration,” said Dr. Galovic and colleagues. The finding that progressive morphologic changes were most pronounced in the first 5 years after epilepsy onset “supports the need for early diagnosis, rapid treatment, and reduction of delays of surgical referral in people with epilepsy,” they added.
One limitation of the current study is the fact that data from patients and controls were acquired using different MRI scanners. In addition, the patients included in the study had been referred to the center because their cases were more complicated, thus introducing the possibility of referral bias. The findings thus cannot be generalized readily to the overall population, said Dr. Galovic and colleagues.
Future studies should examine whether particular AEDs have differential influences on the progressive morphologic changes observed in epilepsy, said the investigators. “Future research should also address whether progressive changes in cortical morphologic characteristics correlate with deficits on serial cognitive testing or spreading of the irritative zone on EEG recordings,” they concluded.
The study and the authors received support from the Medical Research Council, the Wellcome Trust, and the University College London Hospital.
SOURCE: Galovic M et al. JAMA Neurol. 2019 Jul 1. doi: 10.1001/jamaneurol.2019.1708.
, according to research published online July 1 in JAMA Neurology. Methods for preventing this thinning are unknown. “Our findings appear to highlight the need for longitudinal studies to develop disease-modifying treatments for epilepsy,” said Marian Galovic, MD, a doctoral student at University College London, and colleagues.
To date, neurologists have not found a definitive answer to the question of whether epilepsy is a static or progressive disease. Few longitudinal studies have examined patients with structural neuroimaging to determine whether the brain changes over time. The studies that have taken this approach have had small populations or have lacked control populations.
Comparing brain changes in patients and controls
Dr. Galovic and colleagues analyzed data for consecutive patients with focal epilepsy who underwent follow-up at the National Hospital for Neurology and Neurosurgery in London. The data were collected from Aug. 3, 2004, to Jan. 26, 2016. The researchers chose individuals who had at least 2 high-resolution T1-weighted MRI scans performed on the same scanner more than 6 months apart. They excluded patients with brain lesions other than hippocampal sclerosis, those with inadequate MRI scan quality, and those for whom clinical data were missing. To match these patients with controls, Dr. Galovic and colleagues chose three longitudinal data sets with data for healthy volunteers between ages 20 and 70 years. Each control participant had two high-resolution T1-weighted scans taken more than 6 months apart. The investigators matched patients and controls on age and sex. The automated and validated Computational Anatomy Toolbox (CAT12) estimated cortical thickness.
Dr. Galovic’s group included 190 patients with focal epilepsy, who had had 396 MRI scans, and 141 healthy controls, who had had 282 MRI scans, in their analysis. Age, sex, and image quality did not differ significantly between the two groups. Mean age was 36 years for patients and 35 years for controls. The proportion of women was 52.1% among patients and 53.9% among controls.
The rate of atrophy was doubled in patients
Approximately 77% of people with epilepsy had progressive cortical thinning that was distinct from that associated with normal aging. The mean overall annual rate of global cortical thinning was higher among patients with epilepsy (0.024) than among controls (0.011). The mean annual rate of cortical thinning increased among people with epilepsy who were older than 55 years. This rate was 0.021 in patients aged 18 to less than 35 years, compared with 0.023 in patients aged 35 to less than 55 years. Seizure frequency, number of antiepileptic drugs (AEDs) taken, and history of secondarily generalized seizures did not differ between age groups.
Compared with healthy controls, patients with focal epilepsy had widespread areas of greater progressive atrophy. Bilaterally affected areas included the lateral and posterior temporal lobes, posterior cingulate gyri, occipital lobes, pericentral gyri, and opercula. The distribution of progressive thinning in all patients with epilepsy was similar to regions connected to both hippocampi. Healthy controls had no areas of greater cortical thinning, compared with patients with epilepsy.
Progressive thinning in the left postcentral gyrus was greater in patients with left temporal lobe epilepsy (TLE) than in those with right TLE. Cortical thinning was more progressive in patients with right frontal lobe epilepsy (FLE) than in those with left FLE, particularly in right parietotemporal and right frontal areas.
Dr. Galovic and colleagues found no association between the rate of cortical thinning and seizure frequency, history of secondarily generalized seizures, or number of AEDs taken between MRIs. They found no difference in the rate of atrophy between patients with epilepsy with ongoing seizures and those without. The annual mean rate of cortical thinning was higher in people with a short duration of epilepsy (i.e., less than 5 years), compared with patients with a longer duration of epilepsy (i.e., 5 years or more).
A surrogate marker for neurodegeneration?
“The most likely cause of cortical thinning is neuronal loss, suggesting that these measurements are a surrogate marker for neurodegeneration,” said Dr. Galovic and colleagues. The finding that progressive morphologic changes were most pronounced in the first 5 years after epilepsy onset “supports the need for early diagnosis, rapid treatment, and reduction of delays of surgical referral in people with epilepsy,” they added.
One limitation of the current study is the fact that data from patients and controls were acquired using different MRI scanners. In addition, the patients included in the study had been referred to the center because their cases were more complicated, thus introducing the possibility of referral bias. The findings thus cannot be generalized readily to the overall population, said Dr. Galovic and colleagues.
Future studies should examine whether particular AEDs have differential influences on the progressive morphologic changes observed in epilepsy, said the investigators. “Future research should also address whether progressive changes in cortical morphologic characteristics correlate with deficits on serial cognitive testing or spreading of the irritative zone on EEG recordings,” they concluded.
The study and the authors received support from the Medical Research Council, the Wellcome Trust, and the University College London Hospital.
SOURCE: Galovic M et al. JAMA Neurol. 2019 Jul 1. doi: 10.1001/jamaneurol.2019.1708.
FROM JAMA NEUROLOGY
Treatment for pediatric low-grade glioma is associated with poor cognitive and socioeconomic outcomes
Children who underwent surgery alone had better neuropsychologic and socioeconomic outcomes than those who also underwent radiotherapy, but their outcomes were worse than those of unaffected siblings. These findings were published online June 24 in Cancer.
“Late effects in adulthood are evident even for children with the least malignant types of brain tumors who were treated with the least toxic therapies available at the time,” said M. Douglas Ris, PhD, professor of pediatrics and psychology at Baylor College of Medicine in Houston, in a press release. “As pediatric brain tumors become more survivable with continued advances in treatments, we need to improve surveillance of these populations so that survivors continue to receive the best interventions during their transition to adulthood and well beyond.”
Clinicians generally have assumed that children with low-grade CNS tumors who receive less toxic treatment will have fewer long-term effects than survivors of more malignant tumors who undergo neurotoxic therapies. Yet research has indicated that the former patients can have lasting neurobehavioral or functional morbidity.
Dr. Ris and colleagues invited survivors of pediatric low-grade gliomas participating in the Childhood Cancer Survivor Study (CCSS) and a sibling comparison group to undergo a direct, comprehensive neurocognitive assessment. Of 495 eligible survivors, 257 participated. Seventy-six patients did not travel to a study site, but completed a questionnaire, and the researchers did not include data for this group in their analysis. Dr. Ris and colleagues obtained information about surgery and radiotherapy from participants’ medical records. Patients underwent standardized, age-normed neuropsychologic tests. The primary neuropsychologic outcomes were the Composite Neuropsychological Index (CNI) and estimated IQ. To evaluate socioeconomic outcomes, Dr. Ris and colleagues measured participants’ educational attainment, income, and occupational prestige.
After the researchers adjusted the data for age and sex, they found that siblings had higher mean scores than survivors treated with surgery plus radiotherapy or surgery alone on all neuropsychologic outcomes, including the CNI (siblings, 106.8; surgery only, 95.6; surgery plus radiotherapy, 88.3) and estimated IQ. Survivors who had been diagnosed at younger ages had low scores for all outcomes except for attention/processing speed.
Furthermore, surgery plus radiotherapy was associated with a 7.7-fold higher risk of having an occupation in the lowest sibling quartile, compared with siblings. Survivors who underwent surgery alone had a 2.8-fold higher risk than siblings of having an occupation in the lowest quartile. Surgery plus radiotherapy was associated with a 2.6-fold increased risk of a low occupation score, compared with survivors who underwent surgery alone.
Compared with siblings, surgery plus radiotherapy was associated with a 4.5-fold risk of an annual income of less than $20,000, while the risk for survivors who underwent surgery alone did not differ significantly from that for siblings. Surgery plus radiotherapy was associated with a 2.6-fold higher risk than surgery alone. Surgery plus radiotherapy was also associated with a significantly increased risk for an education level lower than a bachelor’s degree, compared with siblings, but surgery alone was not.
The National Cancer Institute supported the study. The authors had no disclosures.
SOURCE: Ris MD et al. Cancer. 2019 Jun 24. doi: 10.1002/cncr.32186.
Children who underwent surgery alone had better neuropsychologic and socioeconomic outcomes than those who also underwent radiotherapy, but their outcomes were worse than those of unaffected siblings. These findings were published online June 24 in Cancer.
“Late effects in adulthood are evident even for children with the least malignant types of brain tumors who were treated with the least toxic therapies available at the time,” said M. Douglas Ris, PhD, professor of pediatrics and psychology at Baylor College of Medicine in Houston, in a press release. “As pediatric brain tumors become more survivable with continued advances in treatments, we need to improve surveillance of these populations so that survivors continue to receive the best interventions during their transition to adulthood and well beyond.”
Clinicians generally have assumed that children with low-grade CNS tumors who receive less toxic treatment will have fewer long-term effects than survivors of more malignant tumors who undergo neurotoxic therapies. Yet research has indicated that the former patients can have lasting neurobehavioral or functional morbidity.
Dr. Ris and colleagues invited survivors of pediatric low-grade gliomas participating in the Childhood Cancer Survivor Study (CCSS) and a sibling comparison group to undergo a direct, comprehensive neurocognitive assessment. Of 495 eligible survivors, 257 participated. Seventy-six patients did not travel to a study site, but completed a questionnaire, and the researchers did not include data for this group in their analysis. Dr. Ris and colleagues obtained information about surgery and radiotherapy from participants’ medical records. Patients underwent standardized, age-normed neuropsychologic tests. The primary neuropsychologic outcomes were the Composite Neuropsychological Index (CNI) and estimated IQ. To evaluate socioeconomic outcomes, Dr. Ris and colleagues measured participants’ educational attainment, income, and occupational prestige.
After the researchers adjusted the data for age and sex, they found that siblings had higher mean scores than survivors treated with surgery plus radiotherapy or surgery alone on all neuropsychologic outcomes, including the CNI (siblings, 106.8; surgery only, 95.6; surgery plus radiotherapy, 88.3) and estimated IQ. Survivors who had been diagnosed at younger ages had low scores for all outcomes except for attention/processing speed.
Furthermore, surgery plus radiotherapy was associated with a 7.7-fold higher risk of having an occupation in the lowest sibling quartile, compared with siblings. Survivors who underwent surgery alone had a 2.8-fold higher risk than siblings of having an occupation in the lowest quartile. Surgery plus radiotherapy was associated with a 2.6-fold increased risk of a low occupation score, compared with survivors who underwent surgery alone.
Compared with siblings, surgery plus radiotherapy was associated with a 4.5-fold risk of an annual income of less than $20,000, while the risk for survivors who underwent surgery alone did not differ significantly from that for siblings. Surgery plus radiotherapy was associated with a 2.6-fold higher risk than surgery alone. Surgery plus radiotherapy was also associated with a significantly increased risk for an education level lower than a bachelor’s degree, compared with siblings, but surgery alone was not.
The National Cancer Institute supported the study. The authors had no disclosures.
SOURCE: Ris MD et al. Cancer. 2019 Jun 24. doi: 10.1002/cncr.32186.
Children who underwent surgery alone had better neuropsychologic and socioeconomic outcomes than those who also underwent radiotherapy, but their outcomes were worse than those of unaffected siblings. These findings were published online June 24 in Cancer.
“Late effects in adulthood are evident even for children with the least malignant types of brain tumors who were treated with the least toxic therapies available at the time,” said M. Douglas Ris, PhD, professor of pediatrics and psychology at Baylor College of Medicine in Houston, in a press release. “As pediatric brain tumors become more survivable with continued advances in treatments, we need to improve surveillance of these populations so that survivors continue to receive the best interventions during their transition to adulthood and well beyond.”
Clinicians generally have assumed that children with low-grade CNS tumors who receive less toxic treatment will have fewer long-term effects than survivors of more malignant tumors who undergo neurotoxic therapies. Yet research has indicated that the former patients can have lasting neurobehavioral or functional morbidity.
Dr. Ris and colleagues invited survivors of pediatric low-grade gliomas participating in the Childhood Cancer Survivor Study (CCSS) and a sibling comparison group to undergo a direct, comprehensive neurocognitive assessment. Of 495 eligible survivors, 257 participated. Seventy-six patients did not travel to a study site, but completed a questionnaire, and the researchers did not include data for this group in their analysis. Dr. Ris and colleagues obtained information about surgery and radiotherapy from participants’ medical records. Patients underwent standardized, age-normed neuropsychologic tests. The primary neuropsychologic outcomes were the Composite Neuropsychological Index (CNI) and estimated IQ. To evaluate socioeconomic outcomes, Dr. Ris and colleagues measured participants’ educational attainment, income, and occupational prestige.
After the researchers adjusted the data for age and sex, they found that siblings had higher mean scores than survivors treated with surgery plus radiotherapy or surgery alone on all neuropsychologic outcomes, including the CNI (siblings, 106.8; surgery only, 95.6; surgery plus radiotherapy, 88.3) and estimated IQ. Survivors who had been diagnosed at younger ages had low scores for all outcomes except for attention/processing speed.
Furthermore, surgery plus radiotherapy was associated with a 7.7-fold higher risk of having an occupation in the lowest sibling quartile, compared with siblings. Survivors who underwent surgery alone had a 2.8-fold higher risk than siblings of having an occupation in the lowest quartile. Surgery plus radiotherapy was associated with a 2.6-fold increased risk of a low occupation score, compared with survivors who underwent surgery alone.
Compared with siblings, surgery plus radiotherapy was associated with a 4.5-fold risk of an annual income of less than $20,000, while the risk for survivors who underwent surgery alone did not differ significantly from that for siblings. Surgery plus radiotherapy was associated with a 2.6-fold higher risk than surgery alone. Surgery plus radiotherapy was also associated with a significantly increased risk for an education level lower than a bachelor’s degree, compared with siblings, but surgery alone was not.
The National Cancer Institute supported the study. The authors had no disclosures.
SOURCE: Ris MD et al. Cancer. 2019 Jun 24. doi: 10.1002/cncr.32186.
FROM CANCER
Age does not influence cladribine’s efficacy in MS
SEATTLE – In addition, age does not affect the likelihood that a patient who receives cladribine will achieve no evidence of disease activity (NEDA), according to a study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
In the phase 3 CLARITY study, a cumulative dose of 3.5 mg/kg of cladribine over 2 years was associated with significantly reduced relapse rate and disability progression and improved MRI outcomes, compared with placebo. The drug’s efficacy persisted in patients who were switched to placebo in a 96-week extension study.
A post hoc analysis
A 2017 study by Weideman et al. suggested that disease-modifying treatment (DMT) is less effective in older patients. For this reason, Gavin Giovannoni, MBBCh, PhD, professor of neurology at Queen Mary University of London, and colleagues decided to investigate the effect of age on the efficacy of treatment with 3.5 mg/kg of cladribine. The investigators performed a post hoc analysis of the CLARITY and CLARITY extension studies of patients with relapsing-remitting MS. They categorized patients as older than 45 years or age 45 years or younger.
Patients enrolled in CLARITY were between ages 18 years and 65 years. They underwent MRI at pretrial assessment and at weeks 24, 48, and 96 or early termination. The investigators defined a qualifying relapse as one associated with changes in Kurtzke Functional Systems score and other specified clinical parameters. Qualifying relapses were confirmed by an independent evaluating physician who was blinded to treatment assignment.
In the CLARITY extension study, 98 participants who had received cladribine tablets 3.5 mg/kg in CLARITY were randomized to placebo for 2 additional years. Participants who continued on placebo in the CLARITY extension were evaluated according to age at entry into CLARITY.
Dr. Giovannoni and colleagues performed efficacy analyses for qualifying relapses; all relapses; and mean and cumulative numbers of new T1 gadolinium-enhancing lesions, active T2 lesions, and combined unique lesions. They defined NEDA as freedom from qualifying relapses, 6-month confirmed disability progression (as measured by the Expanded Disability Status Scale [EDSS] score), T1 gadolinium-enhancing lesions, and active T2 lesions. The investigators performed equivalent analyses for patients who received placebo in the CLARITY extension.
Age did not influence efficacy
Within each age group, participants in both treatment arms had similar baseline demographic and disease characteristics. In CLARITY, 221 patients were older than 45 years, and 649 were age 45 years or younger. In the CLARITY extension, 22 patients were older than 45 years, and 76 were age 45 years or younger. In CLARITY, but not the extension, the proportion of women was higher in the older group than in the younger group (77.7% vs. 66.1%). In CLARITY, patients aged 45 years or younger had a higher number of T1 gadolinium-enhancing lesions at baseline, compared with older patients.
At week 96 in CLARITY, the annual rate of qualifying relapses among patients older than 45 years was 0.14 for cladribine and 0.28 for placebo. Among patients aged 45 or younger, the annual rate of qualifying relapses was 0.15 for cladribine and 0.37 for placebo. For patients older than 45 years, the annual rate of all relapses was 0.28 for cladribine and 0.55 for placebo. For patients aged 45 years or younger, the annual rate of all relapses was 0.26 for cladribine and 0.65 for placebo. The treatment effect of cladribine, compared with placebo, on qualifying relapses and all relapses was similar for both age groups. In the CLARITY extension, the annualized relapse rate (ARR) was 0.17 in patients aged 45 years or younger and 0.05 in patients older than 45 years.
The mean number of new T1 gadolinium-enhancing lesions and cumulative new T1 gadolinium-enhancing lesions was reduced with cladribine, compared with placebo, in both age groups at week 96 in CLARITY. The mean number of active T2 lesions per patient per scan also was significantly reduced with cladribine, compared with placebo, in both age groups. The reduction was 0.167 in patients older than 45 years and 0.667 in patients aged 45 years and younger. In addition, the mean number of combined unique lesions per patient per scan also was significantly reduced with cladribine, compared with placebo, in both age groups. The reduction was 0.333 in patients older than 45 years and 0.667 in patients aged 45 years or younger.
The proportion of participants who achieved NEDA in CLARITY was 55.6% among patients older than 45 years who received cladribine, 39.6% among patients aged 45 years or younger who received cladribine, 28.2% among patients older than 45 years who received placebo, and 9.5% of patients aged 45 years or younger who received placebo. The odds ratio for achieving NEDA was significantly more favorable for the cladribine group, compared with the placebo group, in both age groups (3.19 for patients older than 45 years and 6.23 for patients aged 45 years or younger). In the CLARITY extension, the proportion of participants who achieved NEDA was 40.9% among patients older than 45 years and 28.2% among patients aged 45 years or younger.
“These data are consistent with previous analyses from CLARITY using a different age cutoff and with results from the overall study population,” said Dr. Giovannoni and colleagues.
Merck KGaA, which manufactures and markets cladribine, supported the study. Dr. Giovannoni and several of his coinvestigators have received speaker honoraria, consulting fees, or other funding from companies including Merck KGaA.
SEATTLE – In addition, age does not affect the likelihood that a patient who receives cladribine will achieve no evidence of disease activity (NEDA), according to a study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
In the phase 3 CLARITY study, a cumulative dose of 3.5 mg/kg of cladribine over 2 years was associated with significantly reduced relapse rate and disability progression and improved MRI outcomes, compared with placebo. The drug’s efficacy persisted in patients who were switched to placebo in a 96-week extension study.
A post hoc analysis
A 2017 study by Weideman et al. suggested that disease-modifying treatment (DMT) is less effective in older patients. For this reason, Gavin Giovannoni, MBBCh, PhD, professor of neurology at Queen Mary University of London, and colleagues decided to investigate the effect of age on the efficacy of treatment with 3.5 mg/kg of cladribine. The investigators performed a post hoc analysis of the CLARITY and CLARITY extension studies of patients with relapsing-remitting MS. They categorized patients as older than 45 years or age 45 years or younger.
Patients enrolled in CLARITY were between ages 18 years and 65 years. They underwent MRI at pretrial assessment and at weeks 24, 48, and 96 or early termination. The investigators defined a qualifying relapse as one associated with changes in Kurtzke Functional Systems score and other specified clinical parameters. Qualifying relapses were confirmed by an independent evaluating physician who was blinded to treatment assignment.
In the CLARITY extension study, 98 participants who had received cladribine tablets 3.5 mg/kg in CLARITY were randomized to placebo for 2 additional years. Participants who continued on placebo in the CLARITY extension were evaluated according to age at entry into CLARITY.
Dr. Giovannoni and colleagues performed efficacy analyses for qualifying relapses; all relapses; and mean and cumulative numbers of new T1 gadolinium-enhancing lesions, active T2 lesions, and combined unique lesions. They defined NEDA as freedom from qualifying relapses, 6-month confirmed disability progression (as measured by the Expanded Disability Status Scale [EDSS] score), T1 gadolinium-enhancing lesions, and active T2 lesions. The investigators performed equivalent analyses for patients who received placebo in the CLARITY extension.
Age did not influence efficacy
Within each age group, participants in both treatment arms had similar baseline demographic and disease characteristics. In CLARITY, 221 patients were older than 45 years, and 649 were age 45 years or younger. In the CLARITY extension, 22 patients were older than 45 years, and 76 were age 45 years or younger. In CLARITY, but not the extension, the proportion of women was higher in the older group than in the younger group (77.7% vs. 66.1%). In CLARITY, patients aged 45 years or younger had a higher number of T1 gadolinium-enhancing lesions at baseline, compared with older patients.
At week 96 in CLARITY, the annual rate of qualifying relapses among patients older than 45 years was 0.14 for cladribine and 0.28 for placebo. Among patients aged 45 or younger, the annual rate of qualifying relapses was 0.15 for cladribine and 0.37 for placebo. For patients older than 45 years, the annual rate of all relapses was 0.28 for cladribine and 0.55 for placebo. For patients aged 45 years or younger, the annual rate of all relapses was 0.26 for cladribine and 0.65 for placebo. The treatment effect of cladribine, compared with placebo, on qualifying relapses and all relapses was similar for both age groups. In the CLARITY extension, the annualized relapse rate (ARR) was 0.17 in patients aged 45 years or younger and 0.05 in patients older than 45 years.
The mean number of new T1 gadolinium-enhancing lesions and cumulative new T1 gadolinium-enhancing lesions was reduced with cladribine, compared with placebo, in both age groups at week 96 in CLARITY. The mean number of active T2 lesions per patient per scan also was significantly reduced with cladribine, compared with placebo, in both age groups. The reduction was 0.167 in patients older than 45 years and 0.667 in patients aged 45 years and younger. In addition, the mean number of combined unique lesions per patient per scan also was significantly reduced with cladribine, compared with placebo, in both age groups. The reduction was 0.333 in patients older than 45 years and 0.667 in patients aged 45 years or younger.
The proportion of participants who achieved NEDA in CLARITY was 55.6% among patients older than 45 years who received cladribine, 39.6% among patients aged 45 years or younger who received cladribine, 28.2% among patients older than 45 years who received placebo, and 9.5% of patients aged 45 years or younger who received placebo. The odds ratio for achieving NEDA was significantly more favorable for the cladribine group, compared with the placebo group, in both age groups (3.19 for patients older than 45 years and 6.23 for patients aged 45 years or younger). In the CLARITY extension, the proportion of participants who achieved NEDA was 40.9% among patients older than 45 years and 28.2% among patients aged 45 years or younger.
“These data are consistent with previous analyses from CLARITY using a different age cutoff and with results from the overall study population,” said Dr. Giovannoni and colleagues.
Merck KGaA, which manufactures and markets cladribine, supported the study. Dr. Giovannoni and several of his coinvestigators have received speaker honoraria, consulting fees, or other funding from companies including Merck KGaA.
SEATTLE – In addition, age does not affect the likelihood that a patient who receives cladribine will achieve no evidence of disease activity (NEDA), according to a study presented at the annual meeting of the Consortium of Multiple Sclerosis Centers.
In the phase 3 CLARITY study, a cumulative dose of 3.5 mg/kg of cladribine over 2 years was associated with significantly reduced relapse rate and disability progression and improved MRI outcomes, compared with placebo. The drug’s efficacy persisted in patients who were switched to placebo in a 96-week extension study.
A post hoc analysis
A 2017 study by Weideman et al. suggested that disease-modifying treatment (DMT) is less effective in older patients. For this reason, Gavin Giovannoni, MBBCh, PhD, professor of neurology at Queen Mary University of London, and colleagues decided to investigate the effect of age on the efficacy of treatment with 3.5 mg/kg of cladribine. The investigators performed a post hoc analysis of the CLARITY and CLARITY extension studies of patients with relapsing-remitting MS. They categorized patients as older than 45 years or age 45 years or younger.
Patients enrolled in CLARITY were between ages 18 years and 65 years. They underwent MRI at pretrial assessment and at weeks 24, 48, and 96 or early termination. The investigators defined a qualifying relapse as one associated with changes in Kurtzke Functional Systems score and other specified clinical parameters. Qualifying relapses were confirmed by an independent evaluating physician who was blinded to treatment assignment.
In the CLARITY extension study, 98 participants who had received cladribine tablets 3.5 mg/kg in CLARITY were randomized to placebo for 2 additional years. Participants who continued on placebo in the CLARITY extension were evaluated according to age at entry into CLARITY.
Dr. Giovannoni and colleagues performed efficacy analyses for qualifying relapses; all relapses; and mean and cumulative numbers of new T1 gadolinium-enhancing lesions, active T2 lesions, and combined unique lesions. They defined NEDA as freedom from qualifying relapses, 6-month confirmed disability progression (as measured by the Expanded Disability Status Scale [EDSS] score), T1 gadolinium-enhancing lesions, and active T2 lesions. The investigators performed equivalent analyses for patients who received placebo in the CLARITY extension.
Age did not influence efficacy
Within each age group, participants in both treatment arms had similar baseline demographic and disease characteristics. In CLARITY, 221 patients were older than 45 years, and 649 were age 45 years or younger. In the CLARITY extension, 22 patients were older than 45 years, and 76 were age 45 years or younger. In CLARITY, but not the extension, the proportion of women was higher in the older group than in the younger group (77.7% vs. 66.1%). In CLARITY, patients aged 45 years or younger had a higher number of T1 gadolinium-enhancing lesions at baseline, compared with older patients.
At week 96 in CLARITY, the annual rate of qualifying relapses among patients older than 45 years was 0.14 for cladribine and 0.28 for placebo. Among patients aged 45 or younger, the annual rate of qualifying relapses was 0.15 for cladribine and 0.37 for placebo. For patients older than 45 years, the annual rate of all relapses was 0.28 for cladribine and 0.55 for placebo. For patients aged 45 years or younger, the annual rate of all relapses was 0.26 for cladribine and 0.65 for placebo. The treatment effect of cladribine, compared with placebo, on qualifying relapses and all relapses was similar for both age groups. In the CLARITY extension, the annualized relapse rate (ARR) was 0.17 in patients aged 45 years or younger and 0.05 in patients older than 45 years.
The mean number of new T1 gadolinium-enhancing lesions and cumulative new T1 gadolinium-enhancing lesions was reduced with cladribine, compared with placebo, in both age groups at week 96 in CLARITY. The mean number of active T2 lesions per patient per scan also was significantly reduced with cladribine, compared with placebo, in both age groups. The reduction was 0.167 in patients older than 45 years and 0.667 in patients aged 45 years and younger. In addition, the mean number of combined unique lesions per patient per scan also was significantly reduced with cladribine, compared with placebo, in both age groups. The reduction was 0.333 in patients older than 45 years and 0.667 in patients aged 45 years or younger.
The proportion of participants who achieved NEDA in CLARITY was 55.6% among patients older than 45 years who received cladribine, 39.6% among patients aged 45 years or younger who received cladribine, 28.2% among patients older than 45 years who received placebo, and 9.5% of patients aged 45 years or younger who received placebo. The odds ratio for achieving NEDA was significantly more favorable for the cladribine group, compared with the placebo group, in both age groups (3.19 for patients older than 45 years and 6.23 for patients aged 45 years or younger). In the CLARITY extension, the proportion of participants who achieved NEDA was 40.9% among patients older than 45 years and 28.2% among patients aged 45 years or younger.
“These data are consistent with previous analyses from CLARITY using a different age cutoff and with results from the overall study population,” said Dr. Giovannoni and colleagues.
Merck KGaA, which manufactures and markets cladribine, supported the study. Dr. Giovannoni and several of his coinvestigators have received speaker honoraria, consulting fees, or other funding from companies including Merck KGaA.
REPORTING FROM CMSC 2019
Automated measurements of plasma predict amyloid status
, according to research published online ahead of print June 24 in JAMA Neurology. Analyzing APOE genotype in addition to these biomarkers increases the accuracy of the prediction. This blood test thus could allow neurologists to identify patients at risk of amyloid-beta positivity who should undergo further assessment, said the authors. It also could be used to enroll amyloid-beta–positive participants in clinical trials.
In vivo PET imaging and analysis of cerebrospinal fluid (CSF) can detect amyloid-beta, but these procedures are expensive, and their availability is limited. Clinicians need readily available methods for detecting amyloid-beta, and research has indicated that blood-based biomarkers correlate with those in CSF. Fully automated immunoassays, such as the Elecsys test developed by Roche Diagnostics, have recently demonstrated high reliability and precision for CSF amyloid-beta. Using the Elecsys assay, Sebastian Palmqvist, MD, PhD, a neurologist at Skåne University Hospital in Malmö, Sweden, and colleagues sought to examine the accuracy of plasma amyloid-beta and tau, together with other blood-based biomarkers, at detecting cerebral amyloid-beta.
Testing the immunoassay in two cohorts
Dr. Palmqvist and colleagues examined participants in the prospective Swedish BioFINDER Study, which enrolled patients between July 6, 2009, and February 11, 2015. This cohort included 513 cognitively unimpaired (CU) participants, 265 participants with mild cognitive impairment (MCI), and 64 participants with Alzheimer’s disease dementia. Investigators collected blood and CSF samples at the same time from all participants. Participants’ amyloid-beta status was ascertained using the Elecsys CSF amyloid-beta 42/amyloid-beta 40 ratio. The researchers defined amyloid-beta positivity with an unbiased cutoff of less than 0.059.
Dr. Palmqvist and colleagues also examined a validation cohort that included 237 participants who had been enrolled between January 29, 2000, and October 11, 2006, in Ulm and Hannover, Germany. This group included 34 CU participants, 109 participants with MCI, and 94 participants with mild Alzheimer’s disease dementia. The investigators applied the same cutoff of CSF amyloid-beta 42/amyloid-beta 40 to define amyloid-beta positivity in this cohort as they applied to the BioFINDER cohort.
Automated immunoassay had high predictive accuracy
The mean age of the BioFINDER cohort was 72 years, and 52.5% of participants were female. Overall, 44% of this cohort was amyloid-beta positive, including 29% of CU participants, 60% of participants with MCI, and 100% of participants with Alzheimer’s dementia. The investigators found statistically significant positive correlations between all plasma and corresponding CSF biomarkers in this cohort.
Plasma amyloid-beta 42 and amyloid-beta 40 levels predicted amyloid-beta status with an area under the receiver operating characteristic curve (AUC) of 0.80. When the researchers added APOE to the model, the AUC increased significantly to 0.85. Accuracy improved slightly when the researchers added plasma tau (AUC, 0.86) or tau and neurofilament light (AUC, 0.87) to amyloid-beta 42, amyloid-beta 40, and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants.
In the validation cohort, the mean age was 66 years, and 50.6% of participants were female. When Dr. Palmqvist and colleagues applied the plasma amyloid-beta 42 and amyloid-beta 40 model from the BioFINDER cohort to this population, they obtained a slightly higher AUC (0.86), but plasma tau did not increase predictive accuracy.
The investigators performed a cost-benefit analysis using a scenario in which 1,000 amyloid-positive participants are included in a trial and given a cost of $4,000 per participant for amyloid PET. Using plasma amyloid-beta 42, amyloid-beta 40, and APOE in this scenario reduced PET costs by as much as 30%-50%, depending on the cutoff.
Validation cohort was small
Dr. Palmqvist and colleagues acknowledged that a lack of data about APOE was a limitation of their validation analysis. Other limitations that they acknowledged were the small population size, which precluded subpopulation analysis, and the lack of improvement in predictive ability when they replicated the model that included plasma tau.
“Overall, the accuracies of the amyloid-beta 42 and amyloid-beta 40 assays are not sufficient to be used on their own as a clinical test of amyloid-beta positivity,” said Dr. Palmqvist and colleagues. “Additional assay development is needed before this can be recommended, possibly together with other blood biomarkers and screening tools in diagnostic algorithms.”
Even though additional validation studies are necessary, the present findings indicate “the potential usefulness blood assays might have, especially considering the ongoing great need to recruit large cohorts for Alzheimer’s disease drug trials in preclinical and prodromal stages,” the authors concluded.
This investigation was funded by foundations including the European Research Council, the Swedish Research Council, and the Knut and Alice Wallenberg foundation. Several authors are employees of the Roche Group. One author served on a scientific advisory board for Roche Diagnostics, and another received institutional research support from that company.
SOURCE: Palmqvist S et al. JAMA Neurol. 2019 Jun 24. doi: 10.1001/jamaneurol.2019.1632.
The investigation by Palmqvist et al. “makes several significant advancements in the field,” said Sid E. O’Bryant, PhD, professor of pharmacology and neuroscience at the University of North Texas Health Science Center in Fort Worth, in an accompanying editorial. The study’s protocol design clears the ground for a context of use of a blood screen for amyloid positivity. Also, the fully automated immunoassay “yields performance measurements that are superior to [those of] many earlier nonautomated procedures,” said Dr. O’Bryant. When Dr. Palmqvist and colleagues applied their discovery findings from a training cohort directly to a test cohort, it produced strong results. “This study suggests that the field is one step closer to the actual application of blood-based biomarkers with specific contexts of use in Alzheimer’s disease.”
The main concern about the plasma biomarkers, however, is the scalability of the methods used to measure them. “If primary care physicians are to use such a technology, the technology must have the capacity to conduct hundreds of millions of assays annually around the globe,” said Dr. O’Bryant. “A blood test for primary care must fit into the existing protocols and parameters in clinical laboratory settings. The blood collection and processing procedures are not applicable to standard clinical lab practice and will cause substantial barriers to clinical application.”
In addition, the study authors emphasize the utility of the immunoassay for primary care, but the study was designed to test for amyloid positivity, which is more appropriate for clinical trials. “No currently available drugs for patient use target amyloid,” said Dr. O’Bryant. “Therefore, this specific context of use is geared more toward clinical trial application than primary care physicians who currently need a test for the presence or absence of Alzheimer’s disease so currently available treatments and support can be put in place for patients and family members.”
Nevertheless, Dr. Palmqvist and associates have presented promising data, Dr. O’Bryant continued. The question in the field is ceasing to be whether blood biomarkers can be used in Alzheimer’s disease, and becoming how they can be used.
The investigation by Palmqvist et al. “makes several significant advancements in the field,” said Sid E. O’Bryant, PhD, professor of pharmacology and neuroscience at the University of North Texas Health Science Center in Fort Worth, in an accompanying editorial. The study’s protocol design clears the ground for a context of use of a blood screen for amyloid positivity. Also, the fully automated immunoassay “yields performance measurements that are superior to [those of] many earlier nonautomated procedures,” said Dr. O’Bryant. When Dr. Palmqvist and colleagues applied their discovery findings from a training cohort directly to a test cohort, it produced strong results. “This study suggests that the field is one step closer to the actual application of blood-based biomarkers with specific contexts of use in Alzheimer’s disease.”
The main concern about the plasma biomarkers, however, is the scalability of the methods used to measure them. “If primary care physicians are to use such a technology, the technology must have the capacity to conduct hundreds of millions of assays annually around the globe,” said Dr. O’Bryant. “A blood test for primary care must fit into the existing protocols and parameters in clinical laboratory settings. The blood collection and processing procedures are not applicable to standard clinical lab practice and will cause substantial barriers to clinical application.”
In addition, the study authors emphasize the utility of the immunoassay for primary care, but the study was designed to test for amyloid positivity, which is more appropriate for clinical trials. “No currently available drugs for patient use target amyloid,” said Dr. O’Bryant. “Therefore, this specific context of use is geared more toward clinical trial application than primary care physicians who currently need a test for the presence or absence of Alzheimer’s disease so currently available treatments and support can be put in place for patients and family members.”
Nevertheless, Dr. Palmqvist and associates have presented promising data, Dr. O’Bryant continued. The question in the field is ceasing to be whether blood biomarkers can be used in Alzheimer’s disease, and becoming how they can be used.
The investigation by Palmqvist et al. “makes several significant advancements in the field,” said Sid E. O’Bryant, PhD, professor of pharmacology and neuroscience at the University of North Texas Health Science Center in Fort Worth, in an accompanying editorial. The study’s protocol design clears the ground for a context of use of a blood screen for amyloid positivity. Also, the fully automated immunoassay “yields performance measurements that are superior to [those of] many earlier nonautomated procedures,” said Dr. O’Bryant. When Dr. Palmqvist and colleagues applied their discovery findings from a training cohort directly to a test cohort, it produced strong results. “This study suggests that the field is one step closer to the actual application of blood-based biomarkers with specific contexts of use in Alzheimer’s disease.”
The main concern about the plasma biomarkers, however, is the scalability of the methods used to measure them. “If primary care physicians are to use such a technology, the technology must have the capacity to conduct hundreds of millions of assays annually around the globe,” said Dr. O’Bryant. “A blood test for primary care must fit into the existing protocols and parameters in clinical laboratory settings. The blood collection and processing procedures are not applicable to standard clinical lab practice and will cause substantial barriers to clinical application.”
In addition, the study authors emphasize the utility of the immunoassay for primary care, but the study was designed to test for amyloid positivity, which is more appropriate for clinical trials. “No currently available drugs for patient use target amyloid,” said Dr. O’Bryant. “Therefore, this specific context of use is geared more toward clinical trial application than primary care physicians who currently need a test for the presence or absence of Alzheimer’s disease so currently available treatments and support can be put in place for patients and family members.”
Nevertheless, Dr. Palmqvist and associates have presented promising data, Dr. O’Bryant continued. The question in the field is ceasing to be whether blood biomarkers can be used in Alzheimer’s disease, and becoming how they can be used.
, according to research published online ahead of print June 24 in JAMA Neurology. Analyzing APOE genotype in addition to these biomarkers increases the accuracy of the prediction. This blood test thus could allow neurologists to identify patients at risk of amyloid-beta positivity who should undergo further assessment, said the authors. It also could be used to enroll amyloid-beta–positive participants in clinical trials.
In vivo PET imaging and analysis of cerebrospinal fluid (CSF) can detect amyloid-beta, but these procedures are expensive, and their availability is limited. Clinicians need readily available methods for detecting amyloid-beta, and research has indicated that blood-based biomarkers correlate with those in CSF. Fully automated immunoassays, such as the Elecsys test developed by Roche Diagnostics, have recently demonstrated high reliability and precision for CSF amyloid-beta. Using the Elecsys assay, Sebastian Palmqvist, MD, PhD, a neurologist at Skåne University Hospital in Malmö, Sweden, and colleagues sought to examine the accuracy of plasma amyloid-beta and tau, together with other blood-based biomarkers, at detecting cerebral amyloid-beta.
Testing the immunoassay in two cohorts
Dr. Palmqvist and colleagues examined participants in the prospective Swedish BioFINDER Study, which enrolled patients between July 6, 2009, and February 11, 2015. This cohort included 513 cognitively unimpaired (CU) participants, 265 participants with mild cognitive impairment (MCI), and 64 participants with Alzheimer’s disease dementia. Investigators collected blood and CSF samples at the same time from all participants. Participants’ amyloid-beta status was ascertained using the Elecsys CSF amyloid-beta 42/amyloid-beta 40 ratio. The researchers defined amyloid-beta positivity with an unbiased cutoff of less than 0.059.
Dr. Palmqvist and colleagues also examined a validation cohort that included 237 participants who had been enrolled between January 29, 2000, and October 11, 2006, in Ulm and Hannover, Germany. This group included 34 CU participants, 109 participants with MCI, and 94 participants with mild Alzheimer’s disease dementia. The investigators applied the same cutoff of CSF amyloid-beta 42/amyloid-beta 40 to define amyloid-beta positivity in this cohort as they applied to the BioFINDER cohort.
Automated immunoassay had high predictive accuracy
The mean age of the BioFINDER cohort was 72 years, and 52.5% of participants were female. Overall, 44% of this cohort was amyloid-beta positive, including 29% of CU participants, 60% of participants with MCI, and 100% of participants with Alzheimer’s dementia. The investigators found statistically significant positive correlations between all plasma and corresponding CSF biomarkers in this cohort.
Plasma amyloid-beta 42 and amyloid-beta 40 levels predicted amyloid-beta status with an area under the receiver operating characteristic curve (AUC) of 0.80. When the researchers added APOE to the model, the AUC increased significantly to 0.85. Accuracy improved slightly when the researchers added plasma tau (AUC, 0.86) or tau and neurofilament light (AUC, 0.87) to amyloid-beta 42, amyloid-beta 40, and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants.
In the validation cohort, the mean age was 66 years, and 50.6% of participants were female. When Dr. Palmqvist and colleagues applied the plasma amyloid-beta 42 and amyloid-beta 40 model from the BioFINDER cohort to this population, they obtained a slightly higher AUC (0.86), but plasma tau did not increase predictive accuracy.
The investigators performed a cost-benefit analysis using a scenario in which 1,000 amyloid-positive participants are included in a trial and given a cost of $4,000 per participant for amyloid PET. Using plasma amyloid-beta 42, amyloid-beta 40, and APOE in this scenario reduced PET costs by as much as 30%-50%, depending on the cutoff.
Validation cohort was small
Dr. Palmqvist and colleagues acknowledged that a lack of data about APOE was a limitation of their validation analysis. Other limitations that they acknowledged were the small population size, which precluded subpopulation analysis, and the lack of improvement in predictive ability when they replicated the model that included plasma tau.
“Overall, the accuracies of the amyloid-beta 42 and amyloid-beta 40 assays are not sufficient to be used on their own as a clinical test of amyloid-beta positivity,” said Dr. Palmqvist and colleagues. “Additional assay development is needed before this can be recommended, possibly together with other blood biomarkers and screening tools in diagnostic algorithms.”
Even though additional validation studies are necessary, the present findings indicate “the potential usefulness blood assays might have, especially considering the ongoing great need to recruit large cohorts for Alzheimer’s disease drug trials in preclinical and prodromal stages,” the authors concluded.
This investigation was funded by foundations including the European Research Council, the Swedish Research Council, and the Knut and Alice Wallenberg foundation. Several authors are employees of the Roche Group. One author served on a scientific advisory board for Roche Diagnostics, and another received institutional research support from that company.
SOURCE: Palmqvist S et al. JAMA Neurol. 2019 Jun 24. doi: 10.1001/jamaneurol.2019.1632.
, according to research published online ahead of print June 24 in JAMA Neurology. Analyzing APOE genotype in addition to these biomarkers increases the accuracy of the prediction. This blood test thus could allow neurologists to identify patients at risk of amyloid-beta positivity who should undergo further assessment, said the authors. It also could be used to enroll amyloid-beta–positive participants in clinical trials.
In vivo PET imaging and analysis of cerebrospinal fluid (CSF) can detect amyloid-beta, but these procedures are expensive, and their availability is limited. Clinicians need readily available methods for detecting amyloid-beta, and research has indicated that blood-based biomarkers correlate with those in CSF. Fully automated immunoassays, such as the Elecsys test developed by Roche Diagnostics, have recently demonstrated high reliability and precision for CSF amyloid-beta. Using the Elecsys assay, Sebastian Palmqvist, MD, PhD, a neurologist at Skåne University Hospital in Malmö, Sweden, and colleagues sought to examine the accuracy of plasma amyloid-beta and tau, together with other blood-based biomarkers, at detecting cerebral amyloid-beta.
Testing the immunoassay in two cohorts
Dr. Palmqvist and colleagues examined participants in the prospective Swedish BioFINDER Study, which enrolled patients between July 6, 2009, and February 11, 2015. This cohort included 513 cognitively unimpaired (CU) participants, 265 participants with mild cognitive impairment (MCI), and 64 participants with Alzheimer’s disease dementia. Investigators collected blood and CSF samples at the same time from all participants. Participants’ amyloid-beta status was ascertained using the Elecsys CSF amyloid-beta 42/amyloid-beta 40 ratio. The researchers defined amyloid-beta positivity with an unbiased cutoff of less than 0.059.
Dr. Palmqvist and colleagues also examined a validation cohort that included 237 participants who had been enrolled between January 29, 2000, and October 11, 2006, in Ulm and Hannover, Germany. This group included 34 CU participants, 109 participants with MCI, and 94 participants with mild Alzheimer’s disease dementia. The investigators applied the same cutoff of CSF amyloid-beta 42/amyloid-beta 40 to define amyloid-beta positivity in this cohort as they applied to the BioFINDER cohort.
Automated immunoassay had high predictive accuracy
The mean age of the BioFINDER cohort was 72 years, and 52.5% of participants were female. Overall, 44% of this cohort was amyloid-beta positive, including 29% of CU participants, 60% of participants with MCI, and 100% of participants with Alzheimer’s dementia. The investigators found statistically significant positive correlations between all plasma and corresponding CSF biomarkers in this cohort.
Plasma amyloid-beta 42 and amyloid-beta 40 levels predicted amyloid-beta status with an area under the receiver operating characteristic curve (AUC) of 0.80. When the researchers added APOE to the model, the AUC increased significantly to 0.85. Accuracy improved slightly when the researchers added plasma tau (AUC, 0.86) or tau and neurofilament light (AUC, 0.87) to amyloid-beta 42, amyloid-beta 40, and APOE. The results were similar in CU and cognitively impaired participants, and in younger and older participants.
In the validation cohort, the mean age was 66 years, and 50.6% of participants were female. When Dr. Palmqvist and colleagues applied the plasma amyloid-beta 42 and amyloid-beta 40 model from the BioFINDER cohort to this population, they obtained a slightly higher AUC (0.86), but plasma tau did not increase predictive accuracy.
The investigators performed a cost-benefit analysis using a scenario in which 1,000 amyloid-positive participants are included in a trial and given a cost of $4,000 per participant for amyloid PET. Using plasma amyloid-beta 42, amyloid-beta 40, and APOE in this scenario reduced PET costs by as much as 30%-50%, depending on the cutoff.
Validation cohort was small
Dr. Palmqvist and colleagues acknowledged that a lack of data about APOE was a limitation of their validation analysis. Other limitations that they acknowledged were the small population size, which precluded subpopulation analysis, and the lack of improvement in predictive ability when they replicated the model that included plasma tau.
“Overall, the accuracies of the amyloid-beta 42 and amyloid-beta 40 assays are not sufficient to be used on their own as a clinical test of amyloid-beta positivity,” said Dr. Palmqvist and colleagues. “Additional assay development is needed before this can be recommended, possibly together with other blood biomarkers and screening tools in diagnostic algorithms.”
Even though additional validation studies are necessary, the present findings indicate “the potential usefulness blood assays might have, especially considering the ongoing great need to recruit large cohorts for Alzheimer’s disease drug trials in preclinical and prodromal stages,” the authors concluded.
This investigation was funded by foundations including the European Research Council, the Swedish Research Council, and the Knut and Alice Wallenberg foundation. Several authors are employees of the Roche Group. One author served on a scientific advisory board for Roche Diagnostics, and another received institutional research support from that company.
SOURCE: Palmqvist S et al. JAMA Neurol. 2019 Jun 24. doi: 10.1001/jamaneurol.2019.1632.
FROM JAMA NEUROLOGY
Imaging predicts early postural instability in Parkinson’s disease
PHILADELPHIA – Diffusion-weighted MRI and the presence of at least five of seven clinical features may prove useful for determining which newly diagnosed patients with Parkinson’s disease are likely to have rapidly progressive disease, Frank M. Skidmore, MD, reported at the annual meeting of the American Academy of Neurology.
Patients with gray matter and axonal disease on initial imaging were found to have more aggressive disease associated with early gait dysfunction than were patients with primarily white matter and axonal disease, said Dr. Skidmore, associate professor of neurology at the University of Alabama, Birmingham.
Diffusion-weighted imaging provides a way to assess cellular fluid partitioning and directional information in gray and white matter. Thus, it has the potential to identify brainstem pathology that is associated with disease progression, he said. “Our approach provides a pathway towards using MR to detect early, prognostic, neurodegenerative changes in diseases of the brain.”
Dr. Skidmore and colleagues performed diffusion-weighted imaging on 101 patients with newly diagnosed Parkinson’s disease and 56 healthy controls. They found that Parkinson’s disease was associated with altered radial diffusion in white matter. Changes were observed mainly in the striatonigral tract and the substantia nigra. The investigators also noted atrophy in the cerebellar peduncle among patients with Parkinson’s disease.
At baseline, the patients who went on to have subsequent development of early postural instability and gait dysfunction had decreased intracellular fluid partitioning in the substantia nigra and the mesencephalic locomotor region, which are predominantly gray matter regions. These participants had a lower orientation diffusion index (ODI) and a lower estimate of cellularity, Dr. Skidmore said.
The researchers defined early gait dysfunction as the achievement of a Hoehn and Yahr score of 3 at least once while on medication during the first 5 years after Parkinson’s disease diagnosis. Follow-up was at least 5 years in 79 of the patients.
To identify clinical features associated with early postural instability and gait difficulty, the investigators examined data for 301 patients. In this population, Dr. Skidmore and colleagues identified 218 patients whose Hoehn and Yahr scores never exceeded 2 and 83 patients with at least one Hoehn and Yahr score of 3 or more. Using Bonferroni correction, they examined Unified Parkinson’s Disease Rating Scale (UPDRS) data for all patients to identify significant differences between these two groups. Seven items distinguished patients who developed early postural instability and gait difficulty. They included lightheadedness, fatigue, difficulty walking, ability to rise from a chair, and postural problems. The seven-item scale was superior to the Unified Parkinson’s Disease Rating Scale (UPDRS) at predicting which newly diagnosed patients would develop early postural and gait difficulties
SOURCE: Skidmore F et al. AANN 2019, Abstract S41.004.
PHILADELPHIA – Diffusion-weighted MRI and the presence of at least five of seven clinical features may prove useful for determining which newly diagnosed patients with Parkinson’s disease are likely to have rapidly progressive disease, Frank M. Skidmore, MD, reported at the annual meeting of the American Academy of Neurology.
Patients with gray matter and axonal disease on initial imaging were found to have more aggressive disease associated with early gait dysfunction than were patients with primarily white matter and axonal disease, said Dr. Skidmore, associate professor of neurology at the University of Alabama, Birmingham.
Diffusion-weighted imaging provides a way to assess cellular fluid partitioning and directional information in gray and white matter. Thus, it has the potential to identify brainstem pathology that is associated with disease progression, he said. “Our approach provides a pathway towards using MR to detect early, prognostic, neurodegenerative changes in diseases of the brain.”
Dr. Skidmore and colleagues performed diffusion-weighted imaging on 101 patients with newly diagnosed Parkinson’s disease and 56 healthy controls. They found that Parkinson’s disease was associated with altered radial diffusion in white matter. Changes were observed mainly in the striatonigral tract and the substantia nigra. The investigators also noted atrophy in the cerebellar peduncle among patients with Parkinson’s disease.
At baseline, the patients who went on to have subsequent development of early postural instability and gait dysfunction had decreased intracellular fluid partitioning in the substantia nigra and the mesencephalic locomotor region, which are predominantly gray matter regions. These participants had a lower orientation diffusion index (ODI) and a lower estimate of cellularity, Dr. Skidmore said.
The researchers defined early gait dysfunction as the achievement of a Hoehn and Yahr score of 3 at least once while on medication during the first 5 years after Parkinson’s disease diagnosis. Follow-up was at least 5 years in 79 of the patients.
To identify clinical features associated with early postural instability and gait difficulty, the investigators examined data for 301 patients. In this population, Dr. Skidmore and colleagues identified 218 patients whose Hoehn and Yahr scores never exceeded 2 and 83 patients with at least one Hoehn and Yahr score of 3 or more. Using Bonferroni correction, they examined Unified Parkinson’s Disease Rating Scale (UPDRS) data for all patients to identify significant differences between these two groups. Seven items distinguished patients who developed early postural instability and gait difficulty. They included lightheadedness, fatigue, difficulty walking, ability to rise from a chair, and postural problems. The seven-item scale was superior to the Unified Parkinson’s Disease Rating Scale (UPDRS) at predicting which newly diagnosed patients would develop early postural and gait difficulties
SOURCE: Skidmore F et al. AANN 2019, Abstract S41.004.
PHILADELPHIA – Diffusion-weighted MRI and the presence of at least five of seven clinical features may prove useful for determining which newly diagnosed patients with Parkinson’s disease are likely to have rapidly progressive disease, Frank M. Skidmore, MD, reported at the annual meeting of the American Academy of Neurology.
Patients with gray matter and axonal disease on initial imaging were found to have more aggressive disease associated with early gait dysfunction than were patients with primarily white matter and axonal disease, said Dr. Skidmore, associate professor of neurology at the University of Alabama, Birmingham.
Diffusion-weighted imaging provides a way to assess cellular fluid partitioning and directional information in gray and white matter. Thus, it has the potential to identify brainstem pathology that is associated with disease progression, he said. “Our approach provides a pathway towards using MR to detect early, prognostic, neurodegenerative changes in diseases of the brain.”
Dr. Skidmore and colleagues performed diffusion-weighted imaging on 101 patients with newly diagnosed Parkinson’s disease and 56 healthy controls. They found that Parkinson’s disease was associated with altered radial diffusion in white matter. Changes were observed mainly in the striatonigral tract and the substantia nigra. The investigators also noted atrophy in the cerebellar peduncle among patients with Parkinson’s disease.
At baseline, the patients who went on to have subsequent development of early postural instability and gait dysfunction had decreased intracellular fluid partitioning in the substantia nigra and the mesencephalic locomotor region, which are predominantly gray matter regions. These participants had a lower orientation diffusion index (ODI) and a lower estimate of cellularity, Dr. Skidmore said.
The researchers defined early gait dysfunction as the achievement of a Hoehn and Yahr score of 3 at least once while on medication during the first 5 years after Parkinson’s disease diagnosis. Follow-up was at least 5 years in 79 of the patients.
To identify clinical features associated with early postural instability and gait difficulty, the investigators examined data for 301 patients. In this population, Dr. Skidmore and colleagues identified 218 patients whose Hoehn and Yahr scores never exceeded 2 and 83 patients with at least one Hoehn and Yahr score of 3 or more. Using Bonferroni correction, they examined Unified Parkinson’s Disease Rating Scale (UPDRS) data for all patients to identify significant differences between these two groups. Seven items distinguished patients who developed early postural instability and gait difficulty. They included lightheadedness, fatigue, difficulty walking, ability to rise from a chair, and postural problems. The seven-item scale was superior to the Unified Parkinson’s Disease Rating Scale (UPDRS) at predicting which newly diagnosed patients would develop early postural and gait difficulties
SOURCE: Skidmore F et al. AANN 2019, Abstract S41.004.
REPORTING FROM AAN 2019
CSF neurofilament light level could aid in diagnosis
according to an analysis published online ahead of print June 17 in JAMA Neurology. The biomarker has the potential to distinguish between frontotemporal dementia (FTD) and other dementia subtypes, as well as between Parkinson’s disease and atypical parkinsonian syndromes, said the investigators. It may be necessary to identify age- and sex-specific reference values for NfL, they added.
Neurologists have long understood CSF levels of NfL to be elevated in neurodegenerative conditions, but researchers previously had not compared these levels systematically among neurologic disorders. Similarly, the literature indicates a positive association between CSF NfL level and age in healthy controls, but this association has not been evaluated systematically in neurologic disorders. The resulting lack of clarity has impeded the use of NfL as a diagnostic biomarker.
A meta-analysis of CSF samples
Claire Bridel, MD, PhD, of the department of clinical chemistry at the VU University Medical Centre in Amsterdam and colleagues conducted a systematic review and meta-analysis to compare CSF levels of NfL among diagnoses, assess the associations of age and sex with NfL, and evaluate the potential of NfL as a diagnostic biomarker. The investigators searched PubMed for studies published between Jan. 1, 2006, and Jan. 1, 2016, that reported CSF levels of NfL in neurologic or psychiatric conditions or in healthy controls. They included only studies that used the same commercially available immunoassay that has been used in most studies since 2006. The literature indicates that this enzyme-linked immunosorbent assay is sensitive and robust. Dr. Bridel and colleagues contacted study authors and requested their individual-level data.
The investigators sorted the most common neurologic conditions into three groups of similar disorders. The first group included inflammatory conditions of the CNS, such as multiple sclerosis, clinically isolated syndrome (CIS), and optic neuritis. The second group included dementia syndromes (such as Alzheimer’s disease, FTD, vascular dementia, and dementia with Lewy bodies) and amyotrophic lateral sclerosis (ALS). The third category included parkinsonian syndromes such as Parkinson’s disease, Parkinson’s disease dementia, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The authors used generalized linear mixed-effects models to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels. They modeled cohort of origin as a random intercept.
NfL increased with age
Dr. Bridel and colleagues identified 153 relevant investigations, of which 44 met their inclusion criteria. The original investigators provided data sets for these studies, along with three previously unpublished data sets. The data sets included information from 10,059 participants (mean age, 59.7 years; 54.1% female). After excluding diagnostic categories with fewer than five observations per sex, Dr. Bridel and colleagues included data for 10,012 people in the analysis. In this population, the researchers identified 2,795 patients with inflammatory diseases of the CNS, 4,284 patients with dementia or predementia, 984 patients with parkinsonian disorders, and 1,332 healthy controls.
CSF level of NfL was elevated in most neurologic conditions, compared with healthy controls. The largest effect sizes were in cognitively impaired patients with HIV (21.36), patients with FTD/ALS (10.48), patients with ALS (7.58), and patients with Huntington’s disease (5.88).
In healthy controls, the level of NfL in CSF increased by 3.30% annually. The investigators also observed an association between age and CSF NfL level in people with subjective complaints, bipolar disorder, and most neurodegenerative conditions. They found no association, however, in patients with MS, HIV and cognitive impairment, and rapidly progressive neurodegenerative conditions (such as FTD, ALS, FTD/ALS, MSA, PSP, CBS, and Huntington’s disease). CSF level of NfL was 26.0% higher in men among healthy controls. This discrepancy also was observed in a minority of neurologic conditions, including MS, Alzheimer’s disease, vascular dementia, and Parkinson’s disease.
Mean CSF levels of NfL were similar between patients with inflammatory conditions of the CNS. Among dementias and related disorders, mean CNS level of NfL was significantly higher in FTD than in Alzheimer’s disease (2.08), vascular dementia (1.56), and dementia with Lewy bodies (2.50). Among parkinsonian syndromes, the mean CSF levels of NfL were higher in MSA, PSP, and CBS, compared with Parkinson’s disease.
Many factors influence NfL level in CSF
The association between CNS level of NfL with age among healthy controls “implies that age-specific reference values may be needed and that the diagnostic potential of CSF NfL may decrease with age,” said the researchers. The finding that CSF NfL level was higher in men in a minority of diagnoses has uncertain clinical significance, they added. Sex-specific reference values may be needed.
Dr. Bridel and colleagues found that age, sex, and cohort explained 46% of variation in CSF level of NfL, which suggests that many factors that determine this level have yet to be identified. Disease duration and disease severity could influence the CSF level of NfL, but the data sets that the investigators analyzed did not include this information.
Because CSF NfL level did not differ significantly between relapsing/remitting MS, secondary progressive MS, and primary progressive MS, this biomarker “may not differentiate acute inflammation-induced neuronal damage in the context of relapses from progressive neurodegeneration if the consequences of recent relapses or novel lesion formation are not considered,” said Dr. Bridel and colleagues. The findings do suggest, however, that CSF level of NfL can distinguish FTD from other dementias, as well as Parkinson’s disease from atypical parkinsonian syndromes. Furthermore, it is possible that the findings of this study can be translated to serum level of NfL, said the authors.
One of the study’s limitations was that diagnosis was based on clinical criteria, said Dr. Bridel and colleagues. In addition, the authors were unable to identify dementia of multifactorial origin, which might have reduced the differences in CSF NfL level distributions between dementia subtypes. Finally, the authors only analyzed studies that relied on a specific immunoassay for CSF NfL level.
The authors reported receiving funding from various pharmaceutical and biopharmaceutical companies, as well as from grants and research foundations. The funders did not influence the study design, data analysis, or interpretation, however.
SOURCE: Bridel C et al. JAMA Neurol. 2019 June 17. doi: 10.1001/jamaneurol.2019.1534.
according to an analysis published online ahead of print June 17 in JAMA Neurology. The biomarker has the potential to distinguish between frontotemporal dementia (FTD) and other dementia subtypes, as well as between Parkinson’s disease and atypical parkinsonian syndromes, said the investigators. It may be necessary to identify age- and sex-specific reference values for NfL, they added.
Neurologists have long understood CSF levels of NfL to be elevated in neurodegenerative conditions, but researchers previously had not compared these levels systematically among neurologic disorders. Similarly, the literature indicates a positive association between CSF NfL level and age in healthy controls, but this association has not been evaluated systematically in neurologic disorders. The resulting lack of clarity has impeded the use of NfL as a diagnostic biomarker.
A meta-analysis of CSF samples
Claire Bridel, MD, PhD, of the department of clinical chemistry at the VU University Medical Centre in Amsterdam and colleagues conducted a systematic review and meta-analysis to compare CSF levels of NfL among diagnoses, assess the associations of age and sex with NfL, and evaluate the potential of NfL as a diagnostic biomarker. The investigators searched PubMed for studies published between Jan. 1, 2006, and Jan. 1, 2016, that reported CSF levels of NfL in neurologic or psychiatric conditions or in healthy controls. They included only studies that used the same commercially available immunoassay that has been used in most studies since 2006. The literature indicates that this enzyme-linked immunosorbent assay is sensitive and robust. Dr. Bridel and colleagues contacted study authors and requested their individual-level data.
The investigators sorted the most common neurologic conditions into three groups of similar disorders. The first group included inflammatory conditions of the CNS, such as multiple sclerosis, clinically isolated syndrome (CIS), and optic neuritis. The second group included dementia syndromes (such as Alzheimer’s disease, FTD, vascular dementia, and dementia with Lewy bodies) and amyotrophic lateral sclerosis (ALS). The third category included parkinsonian syndromes such as Parkinson’s disease, Parkinson’s disease dementia, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The authors used generalized linear mixed-effects models to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels. They modeled cohort of origin as a random intercept.
NfL increased with age
Dr. Bridel and colleagues identified 153 relevant investigations, of which 44 met their inclusion criteria. The original investigators provided data sets for these studies, along with three previously unpublished data sets. The data sets included information from 10,059 participants (mean age, 59.7 years; 54.1% female). After excluding diagnostic categories with fewer than five observations per sex, Dr. Bridel and colleagues included data for 10,012 people in the analysis. In this population, the researchers identified 2,795 patients with inflammatory diseases of the CNS, 4,284 patients with dementia or predementia, 984 patients with parkinsonian disorders, and 1,332 healthy controls.
CSF level of NfL was elevated in most neurologic conditions, compared with healthy controls. The largest effect sizes were in cognitively impaired patients with HIV (21.36), patients with FTD/ALS (10.48), patients with ALS (7.58), and patients with Huntington’s disease (5.88).
In healthy controls, the level of NfL in CSF increased by 3.30% annually. The investigators also observed an association between age and CSF NfL level in people with subjective complaints, bipolar disorder, and most neurodegenerative conditions. They found no association, however, in patients with MS, HIV and cognitive impairment, and rapidly progressive neurodegenerative conditions (such as FTD, ALS, FTD/ALS, MSA, PSP, CBS, and Huntington’s disease). CSF level of NfL was 26.0% higher in men among healthy controls. This discrepancy also was observed in a minority of neurologic conditions, including MS, Alzheimer’s disease, vascular dementia, and Parkinson’s disease.
Mean CSF levels of NfL were similar between patients with inflammatory conditions of the CNS. Among dementias and related disorders, mean CNS level of NfL was significantly higher in FTD than in Alzheimer’s disease (2.08), vascular dementia (1.56), and dementia with Lewy bodies (2.50). Among parkinsonian syndromes, the mean CSF levels of NfL were higher in MSA, PSP, and CBS, compared with Parkinson’s disease.
Many factors influence NfL level in CSF
The association between CNS level of NfL with age among healthy controls “implies that age-specific reference values may be needed and that the diagnostic potential of CSF NfL may decrease with age,” said the researchers. The finding that CSF NfL level was higher in men in a minority of diagnoses has uncertain clinical significance, they added. Sex-specific reference values may be needed.
Dr. Bridel and colleagues found that age, sex, and cohort explained 46% of variation in CSF level of NfL, which suggests that many factors that determine this level have yet to be identified. Disease duration and disease severity could influence the CSF level of NfL, but the data sets that the investigators analyzed did not include this information.
Because CSF NfL level did not differ significantly between relapsing/remitting MS, secondary progressive MS, and primary progressive MS, this biomarker “may not differentiate acute inflammation-induced neuronal damage in the context of relapses from progressive neurodegeneration if the consequences of recent relapses or novel lesion formation are not considered,” said Dr. Bridel and colleagues. The findings do suggest, however, that CSF level of NfL can distinguish FTD from other dementias, as well as Parkinson’s disease from atypical parkinsonian syndromes. Furthermore, it is possible that the findings of this study can be translated to serum level of NfL, said the authors.
One of the study’s limitations was that diagnosis was based on clinical criteria, said Dr. Bridel and colleagues. In addition, the authors were unable to identify dementia of multifactorial origin, which might have reduced the differences in CSF NfL level distributions between dementia subtypes. Finally, the authors only analyzed studies that relied on a specific immunoassay for CSF NfL level.
The authors reported receiving funding from various pharmaceutical and biopharmaceutical companies, as well as from grants and research foundations. The funders did not influence the study design, data analysis, or interpretation, however.
SOURCE: Bridel C et al. JAMA Neurol. 2019 June 17. doi: 10.1001/jamaneurol.2019.1534.
according to an analysis published online ahead of print June 17 in JAMA Neurology. The biomarker has the potential to distinguish between frontotemporal dementia (FTD) and other dementia subtypes, as well as between Parkinson’s disease and atypical parkinsonian syndromes, said the investigators. It may be necessary to identify age- and sex-specific reference values for NfL, they added.
Neurologists have long understood CSF levels of NfL to be elevated in neurodegenerative conditions, but researchers previously had not compared these levels systematically among neurologic disorders. Similarly, the literature indicates a positive association between CSF NfL level and age in healthy controls, but this association has not been evaluated systematically in neurologic disorders. The resulting lack of clarity has impeded the use of NfL as a diagnostic biomarker.
A meta-analysis of CSF samples
Claire Bridel, MD, PhD, of the department of clinical chemistry at the VU University Medical Centre in Amsterdam and colleagues conducted a systematic review and meta-analysis to compare CSF levels of NfL among diagnoses, assess the associations of age and sex with NfL, and evaluate the potential of NfL as a diagnostic biomarker. The investigators searched PubMed for studies published between Jan. 1, 2006, and Jan. 1, 2016, that reported CSF levels of NfL in neurologic or psychiatric conditions or in healthy controls. They included only studies that used the same commercially available immunoassay that has been used in most studies since 2006. The literature indicates that this enzyme-linked immunosorbent assay is sensitive and robust. Dr. Bridel and colleagues contacted study authors and requested their individual-level data.
The investigators sorted the most common neurologic conditions into three groups of similar disorders. The first group included inflammatory conditions of the CNS, such as multiple sclerosis, clinically isolated syndrome (CIS), and optic neuritis. The second group included dementia syndromes (such as Alzheimer’s disease, FTD, vascular dementia, and dementia with Lewy bodies) and amyotrophic lateral sclerosis (ALS). The third category included parkinsonian syndromes such as Parkinson’s disease, Parkinson’s disease dementia, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The authors used generalized linear mixed-effects models to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels. They modeled cohort of origin as a random intercept.
NfL increased with age
Dr. Bridel and colleagues identified 153 relevant investigations, of which 44 met their inclusion criteria. The original investigators provided data sets for these studies, along with three previously unpublished data sets. The data sets included information from 10,059 participants (mean age, 59.7 years; 54.1% female). After excluding diagnostic categories with fewer than five observations per sex, Dr. Bridel and colleagues included data for 10,012 people in the analysis. In this population, the researchers identified 2,795 patients with inflammatory diseases of the CNS, 4,284 patients with dementia or predementia, 984 patients with parkinsonian disorders, and 1,332 healthy controls.
CSF level of NfL was elevated in most neurologic conditions, compared with healthy controls. The largest effect sizes were in cognitively impaired patients with HIV (21.36), patients with FTD/ALS (10.48), patients with ALS (7.58), and patients with Huntington’s disease (5.88).
In healthy controls, the level of NfL in CSF increased by 3.30% annually. The investigators also observed an association between age and CSF NfL level in people with subjective complaints, bipolar disorder, and most neurodegenerative conditions. They found no association, however, in patients with MS, HIV and cognitive impairment, and rapidly progressive neurodegenerative conditions (such as FTD, ALS, FTD/ALS, MSA, PSP, CBS, and Huntington’s disease). CSF level of NfL was 26.0% higher in men among healthy controls. This discrepancy also was observed in a minority of neurologic conditions, including MS, Alzheimer’s disease, vascular dementia, and Parkinson’s disease.
Mean CSF levels of NfL were similar between patients with inflammatory conditions of the CNS. Among dementias and related disorders, mean CNS level of NfL was significantly higher in FTD than in Alzheimer’s disease (2.08), vascular dementia (1.56), and dementia with Lewy bodies (2.50). Among parkinsonian syndromes, the mean CSF levels of NfL were higher in MSA, PSP, and CBS, compared with Parkinson’s disease.
Many factors influence NfL level in CSF
The association between CNS level of NfL with age among healthy controls “implies that age-specific reference values may be needed and that the diagnostic potential of CSF NfL may decrease with age,” said the researchers. The finding that CSF NfL level was higher in men in a minority of diagnoses has uncertain clinical significance, they added. Sex-specific reference values may be needed.
Dr. Bridel and colleagues found that age, sex, and cohort explained 46% of variation in CSF level of NfL, which suggests that many factors that determine this level have yet to be identified. Disease duration and disease severity could influence the CSF level of NfL, but the data sets that the investigators analyzed did not include this information.
Because CSF NfL level did not differ significantly between relapsing/remitting MS, secondary progressive MS, and primary progressive MS, this biomarker “may not differentiate acute inflammation-induced neuronal damage in the context of relapses from progressive neurodegeneration if the consequences of recent relapses or novel lesion formation are not considered,” said Dr. Bridel and colleagues. The findings do suggest, however, that CSF level of NfL can distinguish FTD from other dementias, as well as Parkinson’s disease from atypical parkinsonian syndromes. Furthermore, it is possible that the findings of this study can be translated to serum level of NfL, said the authors.
One of the study’s limitations was that diagnosis was based on clinical criteria, said Dr. Bridel and colleagues. In addition, the authors were unable to identify dementia of multifactorial origin, which might have reduced the differences in CSF NfL level distributions between dementia subtypes. Finally, the authors only analyzed studies that relied on a specific immunoassay for CSF NfL level.
The authors reported receiving funding from various pharmaceutical and biopharmaceutical companies, as well as from grants and research foundations. The funders did not influence the study design, data analysis, or interpretation, however.
SOURCE: Bridel C et al. JAMA Neurol. 2019 June 17. doi: 10.1001/jamaneurol.2019.1534.
FROM JAMA NEUROLOGY