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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.
Manual dexterity may decline more rapidly in pediatric-onset MS
WEST PALM BEACH, FLA. – (AOMS), according to an analysis presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
When MS onset occurs before the patient is age 18 years, the patient is considered to have POMS. Compared with AOMS, POMS is less prevalent and has distinct features. To determine whether changes in physical performance differ between POMS and AOMS, Sarah M. Planchon, PhD, a project scientist at the Mellen Center for MS at the Cleveland Clinic, and colleagues analyzed data cut 9 from the MS PATHS (MS Partners Advancing Technology and Health Solutions) initiative. As part of this initiative, which is sponsored by Biogen, investigators collect MS performance measures longitudinally at each patient visit. Among these measures are the manual dexterity test (MDT), an iPad version of the Nine-Hole Peg Test, and the walking speed test (WST), which is the iPad version of the Timed 25-Foot Walk.
Dr. Planchon and colleagues matched each patient with POMS to five patients with AOMS according to disease duration. They calculated descriptive statistics for the sample and performed Tukey’s honestly significant difference test to compare patient groups on several categorical variables.
Overall, function was better in POMS than in AOMS
The investigators included 3 years’ worth of data from 6,457 patients in their analysis. The average age was approximately 50 years for patients with AOMS and 31 years for patients with POMS. The time elapsed since diagnosis was approximately 14 years in the AOMS group and 17 years in the POMS group. The proportion of female patients was about 74% in the AOMS group and 73% in the POMS group. Compared with the AOMS group, the POMS group had higher proportions of patients who were Asian (0.5% vs 2.6%), black (9.3% vs 11.5%), and other race (2.8% vs 9.3%).
Overall, patients with POMS performed better than patients with AOMS by 1.39 seconds on the MDT and by 0.79 seconds on the WST. Regression analyses indicated that with increasing age, patients with AOMS declined more quickly on the MDT and the WST than patients with POMS did. When the investigators stratified the results by disease duration, however, patients with POMS declined more rapidly on the MDT than did patients with AOMS. There was no significant difference between groups in WST in this analysis. When Dr. Planchon and colleagues performed linear regression and adjusted for variables such as age, sex, race, education, insurance, employment, MS phenotype, disease duration, number of relapses, and Patient-Determined Disease Steps (PDDS), the MS onset type did not significantly affect outcomes. Age, sex, PDDS, and MS type were significant covariates for both tests.
The role of occupational and physical therapy
“POMS patients tend to have a greater dysfunction of the cerebellar and brainstem regions of the brain, both of which may impact motor skills to a greater degree than other regions of the brain,” said Dr. Planchon. The increased rate of manual impairment in POMS, compared with AOMS, does not necessarily indicate more severe disease, she added. Getting a true picture of disease severity would require consideration of factors such as ambulation, cognitive functioning, vision, fatigue, and depression.
“We would recommend introducing POMS patients to occupational and physical therapy early in their disease course, before significant deficits accrue,” said Dr. Planchon. “Early familiarity with rehabilitation services should help the patient and family optimize what exercises are being done to improve and maintain function.”
The optimal pharmacologic treatment for POMS is unknown. One therapy (i.e., fingolimod) has Food and Drug Administration approval, and clinical trials of other treatments are ongoing. Some MS treatments not indicated for a pediatric population are used off label in children.
“We plan to delve deeper into the data set, including using regression modeling to try to better define differences between individuals with POMS and AOMS that may lead to the functional outcome changes we have already observed,” said Dr. Planchon. “We also plan to investigate further the impact of POMS on cognition and quality of life measures and to better understand disease-modifying therapy prescribing patterns and benefits in individuals with POMS. We will look for associations in the MRI imaging findings and various biomarkers to help us understand the disease process in this special population of MS.”
Dr. Planchon has received research support from the Guthy-Jackson Charitable Foundation. Her coinvestigators received funding from Biogen, Genentech, Genzyme, MedImmune, Novartis, Serono, and Teva.
SOURCE: Planchon SM et al. ACTRIMS 2020. Abstract P043.
WEST PALM BEACH, FLA. – (AOMS), according to an analysis presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
When MS onset occurs before the patient is age 18 years, the patient is considered to have POMS. Compared with AOMS, POMS is less prevalent and has distinct features. To determine whether changes in physical performance differ between POMS and AOMS, Sarah M. Planchon, PhD, a project scientist at the Mellen Center for MS at the Cleveland Clinic, and colleagues analyzed data cut 9 from the MS PATHS (MS Partners Advancing Technology and Health Solutions) initiative. As part of this initiative, which is sponsored by Biogen, investigators collect MS performance measures longitudinally at each patient visit. Among these measures are the manual dexterity test (MDT), an iPad version of the Nine-Hole Peg Test, and the walking speed test (WST), which is the iPad version of the Timed 25-Foot Walk.
Dr. Planchon and colleagues matched each patient with POMS to five patients with AOMS according to disease duration. They calculated descriptive statistics for the sample and performed Tukey’s honestly significant difference test to compare patient groups on several categorical variables.
Overall, function was better in POMS than in AOMS
The investigators included 3 years’ worth of data from 6,457 patients in their analysis. The average age was approximately 50 years for patients with AOMS and 31 years for patients with POMS. The time elapsed since diagnosis was approximately 14 years in the AOMS group and 17 years in the POMS group. The proportion of female patients was about 74% in the AOMS group and 73% in the POMS group. Compared with the AOMS group, the POMS group had higher proportions of patients who were Asian (0.5% vs 2.6%), black (9.3% vs 11.5%), and other race (2.8% vs 9.3%).
Overall, patients with POMS performed better than patients with AOMS by 1.39 seconds on the MDT and by 0.79 seconds on the WST. Regression analyses indicated that with increasing age, patients with AOMS declined more quickly on the MDT and the WST than patients with POMS did. When the investigators stratified the results by disease duration, however, patients with POMS declined more rapidly on the MDT than did patients with AOMS. There was no significant difference between groups in WST in this analysis. When Dr. Planchon and colleagues performed linear regression and adjusted for variables such as age, sex, race, education, insurance, employment, MS phenotype, disease duration, number of relapses, and Patient-Determined Disease Steps (PDDS), the MS onset type did not significantly affect outcomes. Age, sex, PDDS, and MS type were significant covariates for both tests.
The role of occupational and physical therapy
“POMS patients tend to have a greater dysfunction of the cerebellar and brainstem regions of the brain, both of which may impact motor skills to a greater degree than other regions of the brain,” said Dr. Planchon. The increased rate of manual impairment in POMS, compared with AOMS, does not necessarily indicate more severe disease, she added. Getting a true picture of disease severity would require consideration of factors such as ambulation, cognitive functioning, vision, fatigue, and depression.
“We would recommend introducing POMS patients to occupational and physical therapy early in their disease course, before significant deficits accrue,” said Dr. Planchon. “Early familiarity with rehabilitation services should help the patient and family optimize what exercises are being done to improve and maintain function.”
The optimal pharmacologic treatment for POMS is unknown. One therapy (i.e., fingolimod) has Food and Drug Administration approval, and clinical trials of other treatments are ongoing. Some MS treatments not indicated for a pediatric population are used off label in children.
“We plan to delve deeper into the data set, including using regression modeling to try to better define differences between individuals with POMS and AOMS that may lead to the functional outcome changes we have already observed,” said Dr. Planchon. “We also plan to investigate further the impact of POMS on cognition and quality of life measures and to better understand disease-modifying therapy prescribing patterns and benefits in individuals with POMS. We will look for associations in the MRI imaging findings and various biomarkers to help us understand the disease process in this special population of MS.”
Dr. Planchon has received research support from the Guthy-Jackson Charitable Foundation. Her coinvestigators received funding from Biogen, Genentech, Genzyme, MedImmune, Novartis, Serono, and Teva.
SOURCE: Planchon SM et al. ACTRIMS 2020. Abstract P043.
WEST PALM BEACH, FLA. – (AOMS), according to an analysis presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
When MS onset occurs before the patient is age 18 years, the patient is considered to have POMS. Compared with AOMS, POMS is less prevalent and has distinct features. To determine whether changes in physical performance differ between POMS and AOMS, Sarah M. Planchon, PhD, a project scientist at the Mellen Center for MS at the Cleveland Clinic, and colleagues analyzed data cut 9 from the MS PATHS (MS Partners Advancing Technology and Health Solutions) initiative. As part of this initiative, which is sponsored by Biogen, investigators collect MS performance measures longitudinally at each patient visit. Among these measures are the manual dexterity test (MDT), an iPad version of the Nine-Hole Peg Test, and the walking speed test (WST), which is the iPad version of the Timed 25-Foot Walk.
Dr. Planchon and colleagues matched each patient with POMS to five patients with AOMS according to disease duration. They calculated descriptive statistics for the sample and performed Tukey’s honestly significant difference test to compare patient groups on several categorical variables.
Overall, function was better in POMS than in AOMS
The investigators included 3 years’ worth of data from 6,457 patients in their analysis. The average age was approximately 50 years for patients with AOMS and 31 years for patients with POMS. The time elapsed since diagnosis was approximately 14 years in the AOMS group and 17 years in the POMS group. The proportion of female patients was about 74% in the AOMS group and 73% in the POMS group. Compared with the AOMS group, the POMS group had higher proportions of patients who were Asian (0.5% vs 2.6%), black (9.3% vs 11.5%), and other race (2.8% vs 9.3%).
Overall, patients with POMS performed better than patients with AOMS by 1.39 seconds on the MDT and by 0.79 seconds on the WST. Regression analyses indicated that with increasing age, patients with AOMS declined more quickly on the MDT and the WST than patients with POMS did. When the investigators stratified the results by disease duration, however, patients with POMS declined more rapidly on the MDT than did patients with AOMS. There was no significant difference between groups in WST in this analysis. When Dr. Planchon and colleagues performed linear regression and adjusted for variables such as age, sex, race, education, insurance, employment, MS phenotype, disease duration, number of relapses, and Patient-Determined Disease Steps (PDDS), the MS onset type did not significantly affect outcomes. Age, sex, PDDS, and MS type were significant covariates for both tests.
The role of occupational and physical therapy
“POMS patients tend to have a greater dysfunction of the cerebellar and brainstem regions of the brain, both of which may impact motor skills to a greater degree than other regions of the brain,” said Dr. Planchon. The increased rate of manual impairment in POMS, compared with AOMS, does not necessarily indicate more severe disease, she added. Getting a true picture of disease severity would require consideration of factors such as ambulation, cognitive functioning, vision, fatigue, and depression.
“We would recommend introducing POMS patients to occupational and physical therapy early in their disease course, before significant deficits accrue,” said Dr. Planchon. “Early familiarity with rehabilitation services should help the patient and family optimize what exercises are being done to improve and maintain function.”
The optimal pharmacologic treatment for POMS is unknown. One therapy (i.e., fingolimod) has Food and Drug Administration approval, and clinical trials of other treatments are ongoing. Some MS treatments not indicated for a pediatric population are used off label in children.
“We plan to delve deeper into the data set, including using regression modeling to try to better define differences between individuals with POMS and AOMS that may lead to the functional outcome changes we have already observed,” said Dr. Planchon. “We also plan to investigate further the impact of POMS on cognition and quality of life measures and to better understand disease-modifying therapy prescribing patterns and benefits in individuals with POMS. We will look for associations in the MRI imaging findings and various biomarkers to help us understand the disease process in this special population of MS.”
Dr. Planchon has received research support from the Guthy-Jackson Charitable Foundation. Her coinvestigators received funding from Biogen, Genentech, Genzyme, MedImmune, Novartis, Serono, and Teva.
SOURCE: Planchon SM et al. ACTRIMS 2020. Abstract P043.
REPORTING FROM ACTRIMS FORUM 2020
Serum GFAP may indicate disease severity in NMOSD
WEST PALM BEACH, FLA. – (NMOSD), according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Treatment with inebilizumab decreases serum GFAP concentrations and reduces the risk of an NMOSD attack, the investigators said.
In NMOSD, autoantibodies often target aquaporin-4, a protein expressed on astrocytes. This immune response destroys astrocytes and increases levels of GFAP in cerebrospinal fluid and serum. In the N-MOmentum trial, inebilizumab reduced the risk of attacks by 73%, compared with placebo, in patients with NMOSD. Bruce Cree, MD, PhD, professor of neurology at the University of California, San Francisco, Weill Institute for Neurosciences and colleagues analyzed the data from this trial to examine the relationship between serum GFAP concentrations and disease activity.
In the study, the investigators prospectively collected 1,260 serum samples from 215 participants, 25 healthy donors, and 23 patients with relapsing-remitting multiple sclerosis (MS). Serum GFAP concentration was measured using a single-molecule array assay. The researchers and an independent adjudication committee evaluated attacks during the 28-week randomized controlled study period using predefined criteria.
The median serum GFAP concentration was higher in patients with NMOSD (128.3 pg/mL) than in patients with relapsing-remitting MS (97.5 pg/mL) and healthy controls (73.3 pg/mL). At baseline, 29% of patients with NMOSD and 9% of patients with MS had a serum GFAP concentration that was three or more standard deviations above the mean level in healthy donors.
During the study, patients with a high baseline concentration of serum GFAP were three times more likely to have an adjudicated NMOSD attack than patients with lower serum GFAP concentrations. Concentrations of serum GFAP increased within 1 week of an adjudicated attack during the randomized controlled period. Furthermore, serum GFAP concentration was significantly higher in patients with major adjudicated attacks, compared with those who had minor adjudicated attacks. This finding was true for all organ domains, including for attacks that affected only the optic nerve.
Compared with placebo, inebilizumab reduced the risk of an adjudicated attack by 79% in patients with a normal baseline serum GFAP concentration and by 61% in patients with an elevated baseline serum GFAP concentration. The increase in serum GFAP concentration following an adjudicated attack was significant in patients receiving placebo, but not in patients receiving inebilizumab. Seven samples taken during an adjudicated attack from patients receiving inebilizumab had serum GFAP concentrations within the normal range. One sample taken during an attack from a patient receiving placebo had a serum GFAP concentration within the normal range. In addition, serum GFAP concentrations decreased from baseline among patients receiving inebilizumab who did not have an adjudicated attack.
“These observations suggest that serum GFAP could be a clinically useful biomarker of disease activity and increased attack risk in NMOSD,” said Dr. Cree and colleagues.
Viela Bio, which is developing inebilizumab, and MedImmune sponsored the study. Dr. Cree has received compensation for consulting services that he provided to Alexion, Atara, Biogen, EMD Serono, Novartis, and TG Therapeutics.
SOURCE: Hartung H et al. ACTRIMS 2020, Abstract P205.
WEST PALM BEACH, FLA. – (NMOSD), according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Treatment with inebilizumab decreases serum GFAP concentrations and reduces the risk of an NMOSD attack, the investigators said.
In NMOSD, autoantibodies often target aquaporin-4, a protein expressed on astrocytes. This immune response destroys astrocytes and increases levels of GFAP in cerebrospinal fluid and serum. In the N-MOmentum trial, inebilizumab reduced the risk of attacks by 73%, compared with placebo, in patients with NMOSD. Bruce Cree, MD, PhD, professor of neurology at the University of California, San Francisco, Weill Institute for Neurosciences and colleagues analyzed the data from this trial to examine the relationship between serum GFAP concentrations and disease activity.
In the study, the investigators prospectively collected 1,260 serum samples from 215 participants, 25 healthy donors, and 23 patients with relapsing-remitting multiple sclerosis (MS). Serum GFAP concentration was measured using a single-molecule array assay. The researchers and an independent adjudication committee evaluated attacks during the 28-week randomized controlled study period using predefined criteria.
The median serum GFAP concentration was higher in patients with NMOSD (128.3 pg/mL) than in patients with relapsing-remitting MS (97.5 pg/mL) and healthy controls (73.3 pg/mL). At baseline, 29% of patients with NMOSD and 9% of patients with MS had a serum GFAP concentration that was three or more standard deviations above the mean level in healthy donors.
During the study, patients with a high baseline concentration of serum GFAP were three times more likely to have an adjudicated NMOSD attack than patients with lower serum GFAP concentrations. Concentrations of serum GFAP increased within 1 week of an adjudicated attack during the randomized controlled period. Furthermore, serum GFAP concentration was significantly higher in patients with major adjudicated attacks, compared with those who had minor adjudicated attacks. This finding was true for all organ domains, including for attacks that affected only the optic nerve.
Compared with placebo, inebilizumab reduced the risk of an adjudicated attack by 79% in patients with a normal baseline serum GFAP concentration and by 61% in patients with an elevated baseline serum GFAP concentration. The increase in serum GFAP concentration following an adjudicated attack was significant in patients receiving placebo, but not in patients receiving inebilizumab. Seven samples taken during an adjudicated attack from patients receiving inebilizumab had serum GFAP concentrations within the normal range. One sample taken during an attack from a patient receiving placebo had a serum GFAP concentration within the normal range. In addition, serum GFAP concentrations decreased from baseline among patients receiving inebilizumab who did not have an adjudicated attack.
“These observations suggest that serum GFAP could be a clinically useful biomarker of disease activity and increased attack risk in NMOSD,” said Dr. Cree and colleagues.
Viela Bio, which is developing inebilizumab, and MedImmune sponsored the study. Dr. Cree has received compensation for consulting services that he provided to Alexion, Atara, Biogen, EMD Serono, Novartis, and TG Therapeutics.
SOURCE: Hartung H et al. ACTRIMS 2020, Abstract P205.
WEST PALM BEACH, FLA. – (NMOSD), according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Treatment with inebilizumab decreases serum GFAP concentrations and reduces the risk of an NMOSD attack, the investigators said.
In NMOSD, autoantibodies often target aquaporin-4, a protein expressed on astrocytes. This immune response destroys astrocytes and increases levels of GFAP in cerebrospinal fluid and serum. In the N-MOmentum trial, inebilizumab reduced the risk of attacks by 73%, compared with placebo, in patients with NMOSD. Bruce Cree, MD, PhD, professor of neurology at the University of California, San Francisco, Weill Institute for Neurosciences and colleagues analyzed the data from this trial to examine the relationship between serum GFAP concentrations and disease activity.
In the study, the investigators prospectively collected 1,260 serum samples from 215 participants, 25 healthy donors, and 23 patients with relapsing-remitting multiple sclerosis (MS). Serum GFAP concentration was measured using a single-molecule array assay. The researchers and an independent adjudication committee evaluated attacks during the 28-week randomized controlled study period using predefined criteria.
The median serum GFAP concentration was higher in patients with NMOSD (128.3 pg/mL) than in patients with relapsing-remitting MS (97.5 pg/mL) and healthy controls (73.3 pg/mL). At baseline, 29% of patients with NMOSD and 9% of patients with MS had a serum GFAP concentration that was three or more standard deviations above the mean level in healthy donors.
During the study, patients with a high baseline concentration of serum GFAP were three times more likely to have an adjudicated NMOSD attack than patients with lower serum GFAP concentrations. Concentrations of serum GFAP increased within 1 week of an adjudicated attack during the randomized controlled period. Furthermore, serum GFAP concentration was significantly higher in patients with major adjudicated attacks, compared with those who had minor adjudicated attacks. This finding was true for all organ domains, including for attacks that affected only the optic nerve.
Compared with placebo, inebilizumab reduced the risk of an adjudicated attack by 79% in patients with a normal baseline serum GFAP concentration and by 61% in patients with an elevated baseline serum GFAP concentration. The increase in serum GFAP concentration following an adjudicated attack was significant in patients receiving placebo, but not in patients receiving inebilizumab. Seven samples taken during an adjudicated attack from patients receiving inebilizumab had serum GFAP concentrations within the normal range. One sample taken during an attack from a patient receiving placebo had a serum GFAP concentration within the normal range. In addition, serum GFAP concentrations decreased from baseline among patients receiving inebilizumab who did not have an adjudicated attack.
“These observations suggest that serum GFAP could be a clinically useful biomarker of disease activity and increased attack risk in NMOSD,” said Dr. Cree and colleagues.
Viela Bio, which is developing inebilizumab, and MedImmune sponsored the study. Dr. Cree has received compensation for consulting services that he provided to Alexion, Atara, Biogen, EMD Serono, Novartis, and TG Therapeutics.
SOURCE: Hartung H et al. ACTRIMS 2020, Abstract P205.
REPORTING FROM ACTRIMS FORUM 2020
Age does not appear to affect efficacy of siponimod in secondary progressive MS
WEST PALM BEACH, FLA. – (MS), according to data presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Siponimod’s tolerability also does not vary with age, the researchers said.
Although many effective treatments for relapsing-remitting MS are available, patients still have a high risk of developing secondary progressive MS. Increasing age is associated with disability accumulation, regardless of disease duration. This accumulation of disability could affect treatment outcomes.
Siponimod is an approved treatment for adults with relapsing forms of MS, including clinically isolated syndrome and active secondary progressive MS. Compared with placebo, siponimod significantly reduced the risk of confirmed disability progression in the phase 3 EXPAND trial.
Efficacy was similar between age groups
Le Hua, MD, a neurologist at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, and colleagues sought to evaluate the safety and efficacy of siponimod by age in patients with active secondary progressive MS who participated in the EXPAND study. The investigators defined active disease as a relapse in the 2 years before screening or one or more T1 gadolinium–enhancing lesions at baseline. Time to 3- and 6-month confirmed disability progression, defined using Expanded Disability Status Scale (EDSS) scores, were the efficacy endpoints of this analysis. Dr. Hua and colleagues also examined adverse events, serious adverse events, and adverse events leading to treatment discontinuation.
Of the 1,651 patients included in EXPAND, 779 had active secondary progressive MS. Dr. Hua and colleagues categorized this group as younger than 45 years (306 patients) or 45 years or older (473 patients). In the overall EXPAND population, siponimod reduced the risk of 3-month confirmed disability progression by 21% and the risk of 6-month confirmed disability progression by 26%, compared with placebo. Among patients younger than 45 years, siponimod reduced the risks of 3- and 6-month confirmed disability progression by 32% and 40%, respectively. Among patients aged 45 years or older, siponimod reduced the risks of 3- and 6-month confirmed disability progression by 31% and 33%, respectively.
Siponimod’s safety profile was similar between age groups. Among participants younger than 45 years, the rate of any adverse event was 82.6% for siponimod and 82.8% for placebo. In patients age 45 years or older, the rate of any adverse event was 89.8% for siponimod and 75.9% for placebo. The rate of serious adverse events was lower for siponimod than for placebo in both age groups. Among patients younger than 45 years, the rate was 12.7% for siponimod and 15.1% for placebo. Among patients age 45 years or older, the rate was 18.2% for siponimod and 19.4% for placebo. The rate of adverse events leading to discontinuation, however, was slightly higher among older patients. For younger patients, the rate was 3.3% for siponimod and 4.3% for placebo. For older patients, the rate was 7.6% for siponimod and 7.1% for placebo.
Real-world data will provide clearer answers
Rates of adverse events, serious adverse events, and adverse events leading to discontinuation were all higher in patients aged 45 or older. “This was not a surprising finding,” said Dr. Hua. “The differences appeared small, and the study was not powered to detect if these differences were significant. ... In general, older patients are more likely to have more cardiac events and infections than younger patients.”
Few studies have analyzed the efficacy and safety of MS therapy by age, said Dr. Hua. In 2015, Matell et al. evaluated the effectiveness of natalizumab in patients over age 50 years. In that study, a greater number of older patients, compared with younger patients, stopped treatment because of lack of effectiveness. Studies of other disease-modifying therapies (DMTs) have included subgroup analyses based on age, “but subgroup analyses are limited in the ability to make any strong conclusions regarding significant differences in safety,” said Dr. Hua. “A recent meta-analysis of published clinical trials of all DMTs performed by Weideman et al. indicated that the efficacy of DMTs appears to wane after age 53 years. However, there are limitations in interpreting this data, as they weren’t able to evaluate the raw data. And in most clinical trials, the age cutoff is usually 55 years, which limits generalizations. Real-world data analyses are needed to truly understand efficacy and safety of DMT in older patients.”
Novartis funded the study. Dr. Hua received fees from Novartis, Biogen, Celgene, EMD Serono, Genentech, and Genzyme.
SOURCE: Hua L et al. ACTRIMS FORUM 2020, Abstract P029.
WEST PALM BEACH, FLA. – (MS), according to data presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Siponimod’s tolerability also does not vary with age, the researchers said.
Although many effective treatments for relapsing-remitting MS are available, patients still have a high risk of developing secondary progressive MS. Increasing age is associated with disability accumulation, regardless of disease duration. This accumulation of disability could affect treatment outcomes.
Siponimod is an approved treatment for adults with relapsing forms of MS, including clinically isolated syndrome and active secondary progressive MS. Compared with placebo, siponimod significantly reduced the risk of confirmed disability progression in the phase 3 EXPAND trial.
Efficacy was similar between age groups
Le Hua, MD, a neurologist at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, and colleagues sought to evaluate the safety and efficacy of siponimod by age in patients with active secondary progressive MS who participated in the EXPAND study. The investigators defined active disease as a relapse in the 2 years before screening or one or more T1 gadolinium–enhancing lesions at baseline. Time to 3- and 6-month confirmed disability progression, defined using Expanded Disability Status Scale (EDSS) scores, were the efficacy endpoints of this analysis. Dr. Hua and colleagues also examined adverse events, serious adverse events, and adverse events leading to treatment discontinuation.
Of the 1,651 patients included in EXPAND, 779 had active secondary progressive MS. Dr. Hua and colleagues categorized this group as younger than 45 years (306 patients) or 45 years or older (473 patients). In the overall EXPAND population, siponimod reduced the risk of 3-month confirmed disability progression by 21% and the risk of 6-month confirmed disability progression by 26%, compared with placebo. Among patients younger than 45 years, siponimod reduced the risks of 3- and 6-month confirmed disability progression by 32% and 40%, respectively. Among patients aged 45 years or older, siponimod reduced the risks of 3- and 6-month confirmed disability progression by 31% and 33%, respectively.
Siponimod’s safety profile was similar between age groups. Among participants younger than 45 years, the rate of any adverse event was 82.6% for siponimod and 82.8% for placebo. In patients age 45 years or older, the rate of any adverse event was 89.8% for siponimod and 75.9% for placebo. The rate of serious adverse events was lower for siponimod than for placebo in both age groups. Among patients younger than 45 years, the rate was 12.7% for siponimod and 15.1% for placebo. Among patients age 45 years or older, the rate was 18.2% for siponimod and 19.4% for placebo. The rate of adverse events leading to discontinuation, however, was slightly higher among older patients. For younger patients, the rate was 3.3% for siponimod and 4.3% for placebo. For older patients, the rate was 7.6% for siponimod and 7.1% for placebo.
Real-world data will provide clearer answers
Rates of adverse events, serious adverse events, and adverse events leading to discontinuation were all higher in patients aged 45 or older. “This was not a surprising finding,” said Dr. Hua. “The differences appeared small, and the study was not powered to detect if these differences were significant. ... In general, older patients are more likely to have more cardiac events and infections than younger patients.”
Few studies have analyzed the efficacy and safety of MS therapy by age, said Dr. Hua. In 2015, Matell et al. evaluated the effectiveness of natalizumab in patients over age 50 years. In that study, a greater number of older patients, compared with younger patients, stopped treatment because of lack of effectiveness. Studies of other disease-modifying therapies (DMTs) have included subgroup analyses based on age, “but subgroup analyses are limited in the ability to make any strong conclusions regarding significant differences in safety,” said Dr. Hua. “A recent meta-analysis of published clinical trials of all DMTs performed by Weideman et al. indicated that the efficacy of DMTs appears to wane after age 53 years. However, there are limitations in interpreting this data, as they weren’t able to evaluate the raw data. And in most clinical trials, the age cutoff is usually 55 years, which limits generalizations. Real-world data analyses are needed to truly understand efficacy and safety of DMT in older patients.”
Novartis funded the study. Dr. Hua received fees from Novartis, Biogen, Celgene, EMD Serono, Genentech, and Genzyme.
SOURCE: Hua L et al. ACTRIMS FORUM 2020, Abstract P029.
WEST PALM BEACH, FLA. – (MS), according to data presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. Siponimod’s tolerability also does not vary with age, the researchers said.
Although many effective treatments for relapsing-remitting MS are available, patients still have a high risk of developing secondary progressive MS. Increasing age is associated with disability accumulation, regardless of disease duration. This accumulation of disability could affect treatment outcomes.
Siponimod is an approved treatment for adults with relapsing forms of MS, including clinically isolated syndrome and active secondary progressive MS. Compared with placebo, siponimod significantly reduced the risk of confirmed disability progression in the phase 3 EXPAND trial.
Efficacy was similar between age groups
Le Hua, MD, a neurologist at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, and colleagues sought to evaluate the safety and efficacy of siponimod by age in patients with active secondary progressive MS who participated in the EXPAND study. The investigators defined active disease as a relapse in the 2 years before screening or one or more T1 gadolinium–enhancing lesions at baseline. Time to 3- and 6-month confirmed disability progression, defined using Expanded Disability Status Scale (EDSS) scores, were the efficacy endpoints of this analysis. Dr. Hua and colleagues also examined adverse events, serious adverse events, and adverse events leading to treatment discontinuation.
Of the 1,651 patients included in EXPAND, 779 had active secondary progressive MS. Dr. Hua and colleagues categorized this group as younger than 45 years (306 patients) or 45 years or older (473 patients). In the overall EXPAND population, siponimod reduced the risk of 3-month confirmed disability progression by 21% and the risk of 6-month confirmed disability progression by 26%, compared with placebo. Among patients younger than 45 years, siponimod reduced the risks of 3- and 6-month confirmed disability progression by 32% and 40%, respectively. Among patients aged 45 years or older, siponimod reduced the risks of 3- and 6-month confirmed disability progression by 31% and 33%, respectively.
Siponimod’s safety profile was similar between age groups. Among participants younger than 45 years, the rate of any adverse event was 82.6% for siponimod and 82.8% for placebo. In patients age 45 years or older, the rate of any adverse event was 89.8% for siponimod and 75.9% for placebo. The rate of serious adverse events was lower for siponimod than for placebo in both age groups. Among patients younger than 45 years, the rate was 12.7% for siponimod and 15.1% for placebo. Among patients age 45 years or older, the rate was 18.2% for siponimod and 19.4% for placebo. The rate of adverse events leading to discontinuation, however, was slightly higher among older patients. For younger patients, the rate was 3.3% for siponimod and 4.3% for placebo. For older patients, the rate was 7.6% for siponimod and 7.1% for placebo.
Real-world data will provide clearer answers
Rates of adverse events, serious adverse events, and adverse events leading to discontinuation were all higher in patients aged 45 or older. “This was not a surprising finding,” said Dr. Hua. “The differences appeared small, and the study was not powered to detect if these differences were significant. ... In general, older patients are more likely to have more cardiac events and infections than younger patients.”
Few studies have analyzed the efficacy and safety of MS therapy by age, said Dr. Hua. In 2015, Matell et al. evaluated the effectiveness of natalizumab in patients over age 50 years. In that study, a greater number of older patients, compared with younger patients, stopped treatment because of lack of effectiveness. Studies of other disease-modifying therapies (DMTs) have included subgroup analyses based on age, “but subgroup analyses are limited in the ability to make any strong conclusions regarding significant differences in safety,” said Dr. Hua. “A recent meta-analysis of published clinical trials of all DMTs performed by Weideman et al. indicated that the efficacy of DMTs appears to wane after age 53 years. However, there are limitations in interpreting this data, as they weren’t able to evaluate the raw data. And in most clinical trials, the age cutoff is usually 55 years, which limits generalizations. Real-world data analyses are needed to truly understand efficacy and safety of DMT in older patients.”
Novartis funded the study. Dr. Hua received fees from Novartis, Biogen, Celgene, EMD Serono, Genentech, and Genzyme.
SOURCE: Hua L et al. ACTRIMS FORUM 2020, Abstract P029.
REPORTING FROM ACTRIMS FORUM 2020
Inebilizumab benefits patients with NMOSD
WEST PALM BEACH, FLA. – Compared with placebo, inebilizumab reduces the risk of attacks, the risk of disability worsening, the number of hospitalizations, and the number of new MRI lesions in patients with neuromyelitis optica spectrum disorder (NMOSD), according to a study presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The drug’s efficacy was sustained for one year in the study, and the treatment had an acceptable safety profile.
“Multiple lines of evidence suggest that NMO is predominantly a B-cell–mediated disorder,” said Bruce Cree, MD, PhD, professor of neurology at the University of California, San Francisco, Weill Institute for Neurosciences. Inebilizumab depletes B cells and reduces inflammatory disease activity in NMO potentially by altering immune networks that are dependent on B cells for cytokine production or antigen presentation.” Inebilizumab is an anti-CD19 monoclonal antibody.
Dr. Cree and colleagues conducted a randomized, controlled trial called N-MOmentum to characterize the long-term efficacy and safety of inebilizumab in patients with NMOSD. The investigators randomized patients with NMOSD to inebilizumab or placebo monotherapy in a 3:1 ratio for 6.5 months. The study’s primary outcome was the time to the first adjudicated attack. Patients who had an adjudicated attack or completed the trial could receive inebilizumab in an ongoing open-label extension.
The study was conducted at 99 sites in 25 countries. In all, 230 patients were randomized and dosed (174 received inebilizumab, and 56 received placebo). About 91% of the population was aquaporin-4-IgG–positive (AQP4-IgG+), and 91% was female. The population’s mean age at baseline was 43 years. The population’s median baseline Expanded Disability Status Scale score was approximately 3.5, and the range was from 0 to 8.0. Approximately 50% of participants were white, 20% were Asian, and 9% were of African descent. “The demographic profile is similar to that of many published studies,” said Dr. Cree.
Because of clear evidence of efficacy, the independent data monitoring committee recommended that the study be stopped early. In the randomized, controlled trial, inebilizumab reduced the risk of attack by 77.3% among AQP4-IgG+ patients and by 72.8% in the total population. The number needed to treat for 6.5 months to prevent one attack was 3.2 for the AQP4-IgG+ group and 3.7 for the total population.
Furthermore, inebilizumab significantly reduced the risk of worsening disability, the number of new MRI lesions, and NMOSD-related hospitalizations. After 1 year on inebilizumab, 85% of patients were free of an NMOSD attack. In safety analyses that combined data from the randomized, controlled trial and interim data from the open-label extension, the mean duration of inebilizumab treatment was 1.5 years.
“The rapid effect of inebilizumab on attack prevention is not mediated by decreasing AQP4-IgG, although it is possible that long-term inebilizumab treatment might eventually reduce AQP4-IgG production,” said Dr. Cree.
The most common adverse events (AEs) were urinary tract infection (UTI, 19.6%), nasopharyngitis (12.9%), and infusion-related reactions (IRRs, 11.6%). IRRs were most common with the first infusion. The proportion of inebilizumab-treated patients with IgG levels below the lower limit of normal was 7.5% at 1 year and 13.4% at 2 years. Serious AEs occurred in 12% of patients, and UTI was the most common (2.2%). Two patients died in the open-label extension; one death resulted from NMOSD, and one from new presumed inflammatory brain lesions of undetermined etiology.
“The open-label results show a striking durability of treatment effect,” said Dr. Cree. “Most of the attacks that occurred during the open-label extension occurred early on, suggesting that the risk of attack decreases with duration of B-cell depletion. The open-label study also is important for assessing the longer-term AE profile of inebilizumab treatment. One potentially important observation from the open-label extension is that the extent of B-cell depletion correlates with reduced attack risk. Approximately 95% of participants with deep B-cell depletion were free of attacks. Participants who either incompletely depleted B cells or who began to reconstitute B cells more rapidly were at increased risk of attack. Therefore, by monitoring B-cell counts in inebilizumab-treated patients, it may be possible to further reduce the risk of attack in patients who partially deplete, or replete B cells early, with an extra inebilizumab treatment.”
Viela Bio, which is developing inebilizumab, and MedImmune sponsored the study. Dr. Cree has received compensation for consulting services that he provided to Alexion, Atara, Biogen, EMD Serono, Novartis, and TG Therapeutics.
SOURCE: Cree BA et al. ACTRIMS 2020. Abstract P207.
WEST PALM BEACH, FLA. – Compared with placebo, inebilizumab reduces the risk of attacks, the risk of disability worsening, the number of hospitalizations, and the number of new MRI lesions in patients with neuromyelitis optica spectrum disorder (NMOSD), according to a study presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The drug’s efficacy was sustained for one year in the study, and the treatment had an acceptable safety profile.
“Multiple lines of evidence suggest that NMO is predominantly a B-cell–mediated disorder,” said Bruce Cree, MD, PhD, professor of neurology at the University of California, San Francisco, Weill Institute for Neurosciences. Inebilizumab depletes B cells and reduces inflammatory disease activity in NMO potentially by altering immune networks that are dependent on B cells for cytokine production or antigen presentation.” Inebilizumab is an anti-CD19 monoclonal antibody.
Dr. Cree and colleagues conducted a randomized, controlled trial called N-MOmentum to characterize the long-term efficacy and safety of inebilizumab in patients with NMOSD. The investigators randomized patients with NMOSD to inebilizumab or placebo monotherapy in a 3:1 ratio for 6.5 months. The study’s primary outcome was the time to the first adjudicated attack. Patients who had an adjudicated attack or completed the trial could receive inebilizumab in an ongoing open-label extension.
The study was conducted at 99 sites in 25 countries. In all, 230 patients were randomized and dosed (174 received inebilizumab, and 56 received placebo). About 91% of the population was aquaporin-4-IgG–positive (AQP4-IgG+), and 91% was female. The population’s mean age at baseline was 43 years. The population’s median baseline Expanded Disability Status Scale score was approximately 3.5, and the range was from 0 to 8.0. Approximately 50% of participants were white, 20% were Asian, and 9% were of African descent. “The demographic profile is similar to that of many published studies,” said Dr. Cree.
Because of clear evidence of efficacy, the independent data monitoring committee recommended that the study be stopped early. In the randomized, controlled trial, inebilizumab reduced the risk of attack by 77.3% among AQP4-IgG+ patients and by 72.8% in the total population. The number needed to treat for 6.5 months to prevent one attack was 3.2 for the AQP4-IgG+ group and 3.7 for the total population.
Furthermore, inebilizumab significantly reduced the risk of worsening disability, the number of new MRI lesions, and NMOSD-related hospitalizations. After 1 year on inebilizumab, 85% of patients were free of an NMOSD attack. In safety analyses that combined data from the randomized, controlled trial and interim data from the open-label extension, the mean duration of inebilizumab treatment was 1.5 years.
“The rapid effect of inebilizumab on attack prevention is not mediated by decreasing AQP4-IgG, although it is possible that long-term inebilizumab treatment might eventually reduce AQP4-IgG production,” said Dr. Cree.
The most common adverse events (AEs) were urinary tract infection (UTI, 19.6%), nasopharyngitis (12.9%), and infusion-related reactions (IRRs, 11.6%). IRRs were most common with the first infusion. The proportion of inebilizumab-treated patients with IgG levels below the lower limit of normal was 7.5% at 1 year and 13.4% at 2 years. Serious AEs occurred in 12% of patients, and UTI was the most common (2.2%). Two patients died in the open-label extension; one death resulted from NMOSD, and one from new presumed inflammatory brain lesions of undetermined etiology.
“The open-label results show a striking durability of treatment effect,” said Dr. Cree. “Most of the attacks that occurred during the open-label extension occurred early on, suggesting that the risk of attack decreases with duration of B-cell depletion. The open-label study also is important for assessing the longer-term AE profile of inebilizumab treatment. One potentially important observation from the open-label extension is that the extent of B-cell depletion correlates with reduced attack risk. Approximately 95% of participants with deep B-cell depletion were free of attacks. Participants who either incompletely depleted B cells or who began to reconstitute B cells more rapidly were at increased risk of attack. Therefore, by monitoring B-cell counts in inebilizumab-treated patients, it may be possible to further reduce the risk of attack in patients who partially deplete, or replete B cells early, with an extra inebilizumab treatment.”
Viela Bio, which is developing inebilizumab, and MedImmune sponsored the study. Dr. Cree has received compensation for consulting services that he provided to Alexion, Atara, Biogen, EMD Serono, Novartis, and TG Therapeutics.
SOURCE: Cree BA et al. ACTRIMS 2020. Abstract P207.
WEST PALM BEACH, FLA. – Compared with placebo, inebilizumab reduces the risk of attacks, the risk of disability worsening, the number of hospitalizations, and the number of new MRI lesions in patients with neuromyelitis optica spectrum disorder (NMOSD), according to a study presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The drug’s efficacy was sustained for one year in the study, and the treatment had an acceptable safety profile.
“Multiple lines of evidence suggest that NMO is predominantly a B-cell–mediated disorder,” said Bruce Cree, MD, PhD, professor of neurology at the University of California, San Francisco, Weill Institute for Neurosciences. Inebilizumab depletes B cells and reduces inflammatory disease activity in NMO potentially by altering immune networks that are dependent on B cells for cytokine production or antigen presentation.” Inebilizumab is an anti-CD19 monoclonal antibody.
Dr. Cree and colleagues conducted a randomized, controlled trial called N-MOmentum to characterize the long-term efficacy and safety of inebilizumab in patients with NMOSD. The investigators randomized patients with NMOSD to inebilizumab or placebo monotherapy in a 3:1 ratio for 6.5 months. The study’s primary outcome was the time to the first adjudicated attack. Patients who had an adjudicated attack or completed the trial could receive inebilizumab in an ongoing open-label extension.
The study was conducted at 99 sites in 25 countries. In all, 230 patients were randomized and dosed (174 received inebilizumab, and 56 received placebo). About 91% of the population was aquaporin-4-IgG–positive (AQP4-IgG+), and 91% was female. The population’s mean age at baseline was 43 years. The population’s median baseline Expanded Disability Status Scale score was approximately 3.5, and the range was from 0 to 8.0. Approximately 50% of participants were white, 20% were Asian, and 9% were of African descent. “The demographic profile is similar to that of many published studies,” said Dr. Cree.
Because of clear evidence of efficacy, the independent data monitoring committee recommended that the study be stopped early. In the randomized, controlled trial, inebilizumab reduced the risk of attack by 77.3% among AQP4-IgG+ patients and by 72.8% in the total population. The number needed to treat for 6.5 months to prevent one attack was 3.2 for the AQP4-IgG+ group and 3.7 for the total population.
Furthermore, inebilizumab significantly reduced the risk of worsening disability, the number of new MRI lesions, and NMOSD-related hospitalizations. After 1 year on inebilizumab, 85% of patients were free of an NMOSD attack. In safety analyses that combined data from the randomized, controlled trial and interim data from the open-label extension, the mean duration of inebilizumab treatment was 1.5 years.
“The rapid effect of inebilizumab on attack prevention is not mediated by decreasing AQP4-IgG, although it is possible that long-term inebilizumab treatment might eventually reduce AQP4-IgG production,” said Dr. Cree.
The most common adverse events (AEs) were urinary tract infection (UTI, 19.6%), nasopharyngitis (12.9%), and infusion-related reactions (IRRs, 11.6%). IRRs were most common with the first infusion. The proportion of inebilizumab-treated patients with IgG levels below the lower limit of normal was 7.5% at 1 year and 13.4% at 2 years. Serious AEs occurred in 12% of patients, and UTI was the most common (2.2%). Two patients died in the open-label extension; one death resulted from NMOSD, and one from new presumed inflammatory brain lesions of undetermined etiology.
“The open-label results show a striking durability of treatment effect,” said Dr. Cree. “Most of the attacks that occurred during the open-label extension occurred early on, suggesting that the risk of attack decreases with duration of B-cell depletion. The open-label study also is important for assessing the longer-term AE profile of inebilizumab treatment. One potentially important observation from the open-label extension is that the extent of B-cell depletion correlates with reduced attack risk. Approximately 95% of participants with deep B-cell depletion were free of attacks. Participants who either incompletely depleted B cells or who began to reconstitute B cells more rapidly were at increased risk of attack. Therefore, by monitoring B-cell counts in inebilizumab-treated patients, it may be possible to further reduce the risk of attack in patients who partially deplete, or replete B cells early, with an extra inebilizumab treatment.”
Viela Bio, which is developing inebilizumab, and MedImmune sponsored the study. Dr. Cree has received compensation for consulting services that he provided to Alexion, Atara, Biogen, EMD Serono, Novartis, and TG Therapeutics.
SOURCE: Cree BA et al. ACTRIMS 2020. Abstract P207.
REPORTING FROM ACTRIMS FORUM 2020
Eculizumab reduces relapse-related hospitalizations in patients with NMOSD
WEST PALM BEACH, FLA. – , according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The results suggest that eculizumab may have a favorable effect on health-resource utilization.
Many patients with NMOSD, a rare autoimmune inflammatory disease, have relapses that result in hospitalization. Eculizumab (Soliris)is a humanized monoclonal antibody that inhibits the terminal complement protein C5. In the randomized, double-blind, placebo-controlled PREVENT study, Dean M. Wingerchuk, MD, chair of neurology at Mayo Clinic in Phoenix, , and colleagues found that eculizumab was associated with a 94% reduction in the risk of relapse, compared with placebo, in AQP4-IgG-positive patients with NMOSD.
In a new analysis of the PREVENT data, the investigators sought to evaluate rates of relapse-related hospitalization and associated treatment among study participants. The researchers chose time to first adjudicated relapse as their primary endpoint.
In the PREVENT study, Dr. Wingerchuk and colleagues randomized patients with AQP4-IgG-positive NMOSD to eculizumab (1,200 mg/2 weeks) or placebo. The annualized relapse-related hospitalization and treatment rates were calculated as the number of relapses requiring hospitalization or treatment divided by the total number of patient-years during the study.
Approximately 91% of participants were female. Mean age at initial clinical presentation was about 37 years. Participants’ median Expanded Disability Status Scale score at baseline was 4, and their mean annualized relapse rate in the 24 months before screening was 2. In all, 96 patients received eculizumab, and 47 received placebo. The median length of exposure to treatment was 89.4 weeks in the eculizumab group and 41.3 weeks among controls.
The rate of adverse events requiring hospitalization was 29% in the eculizumab group and 53% in the placebo group. The most common events requiring hospitalization were physician-determined relapses. Infections were the next most common events requiring hospitalization.
The overall annualized hospitalization rate was 0.26 in the eculizumab group and 0.78 in the placebo group. The difference between groups was statistically significant. In addition, the annualized relapse-related hospitalization rate was lower in the eculizumab group than in the placebo group (0.04 vs. 0.31, respectively).
The annualized relapse-related use of intravenous methylprednisolone for the eculizumab and placebo groups were 0.07 and 0.42, respectively; for use of plasma exchange, 0.02 and 0.19; and for use of high-dose oral corticosteroids, 0.04 and 0.11. The differences between groups in use of intravenous methylprednisolone and plasma exchange were statistically significant.
Alexion Pharmaceuticals, which markets eculizumab, sponsored the study. Dr. Wingerchuk received grants from Alexion during the study. He also received personal fees from Biogen, BrainStorm Therapeutics, Celgene, MedImmune, Novartis, and ONO Pharmaceutical.
SOURCE: Kim H et al. ACTRIMS 2020. Abstract P197.
WEST PALM BEACH, FLA. – , according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The results suggest that eculizumab may have a favorable effect on health-resource utilization.
Many patients with NMOSD, a rare autoimmune inflammatory disease, have relapses that result in hospitalization. Eculizumab (Soliris)is a humanized monoclonal antibody that inhibits the terminal complement protein C5. In the randomized, double-blind, placebo-controlled PREVENT study, Dean M. Wingerchuk, MD, chair of neurology at Mayo Clinic in Phoenix, , and colleagues found that eculizumab was associated with a 94% reduction in the risk of relapse, compared with placebo, in AQP4-IgG-positive patients with NMOSD.
In a new analysis of the PREVENT data, the investigators sought to evaluate rates of relapse-related hospitalization and associated treatment among study participants. The researchers chose time to first adjudicated relapse as their primary endpoint.
In the PREVENT study, Dr. Wingerchuk and colleagues randomized patients with AQP4-IgG-positive NMOSD to eculizumab (1,200 mg/2 weeks) or placebo. The annualized relapse-related hospitalization and treatment rates were calculated as the number of relapses requiring hospitalization or treatment divided by the total number of patient-years during the study.
Approximately 91% of participants were female. Mean age at initial clinical presentation was about 37 years. Participants’ median Expanded Disability Status Scale score at baseline was 4, and their mean annualized relapse rate in the 24 months before screening was 2. In all, 96 patients received eculizumab, and 47 received placebo. The median length of exposure to treatment was 89.4 weeks in the eculizumab group and 41.3 weeks among controls.
The rate of adverse events requiring hospitalization was 29% in the eculizumab group and 53% in the placebo group. The most common events requiring hospitalization were physician-determined relapses. Infections were the next most common events requiring hospitalization.
The overall annualized hospitalization rate was 0.26 in the eculizumab group and 0.78 in the placebo group. The difference between groups was statistically significant. In addition, the annualized relapse-related hospitalization rate was lower in the eculizumab group than in the placebo group (0.04 vs. 0.31, respectively).
The annualized relapse-related use of intravenous methylprednisolone for the eculizumab and placebo groups were 0.07 and 0.42, respectively; for use of plasma exchange, 0.02 and 0.19; and for use of high-dose oral corticosteroids, 0.04 and 0.11. The differences between groups in use of intravenous methylprednisolone and plasma exchange were statistically significant.
Alexion Pharmaceuticals, which markets eculizumab, sponsored the study. Dr. Wingerchuk received grants from Alexion during the study. He also received personal fees from Biogen, BrainStorm Therapeutics, Celgene, MedImmune, Novartis, and ONO Pharmaceutical.
SOURCE: Kim H et al. ACTRIMS 2020. Abstract P197.
WEST PALM BEACH, FLA. – , according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The results suggest that eculizumab may have a favorable effect on health-resource utilization.
Many patients with NMOSD, a rare autoimmune inflammatory disease, have relapses that result in hospitalization. Eculizumab (Soliris)is a humanized monoclonal antibody that inhibits the terminal complement protein C5. In the randomized, double-blind, placebo-controlled PREVENT study, Dean M. Wingerchuk, MD, chair of neurology at Mayo Clinic in Phoenix, , and colleagues found that eculizumab was associated with a 94% reduction in the risk of relapse, compared with placebo, in AQP4-IgG-positive patients with NMOSD.
In a new analysis of the PREVENT data, the investigators sought to evaluate rates of relapse-related hospitalization and associated treatment among study participants. The researchers chose time to first adjudicated relapse as their primary endpoint.
In the PREVENT study, Dr. Wingerchuk and colleagues randomized patients with AQP4-IgG-positive NMOSD to eculizumab (1,200 mg/2 weeks) or placebo. The annualized relapse-related hospitalization and treatment rates were calculated as the number of relapses requiring hospitalization or treatment divided by the total number of patient-years during the study.
Approximately 91% of participants were female. Mean age at initial clinical presentation was about 37 years. Participants’ median Expanded Disability Status Scale score at baseline was 4, and their mean annualized relapse rate in the 24 months before screening was 2. In all, 96 patients received eculizumab, and 47 received placebo. The median length of exposure to treatment was 89.4 weeks in the eculizumab group and 41.3 weeks among controls.
The rate of adverse events requiring hospitalization was 29% in the eculizumab group and 53% in the placebo group. The most common events requiring hospitalization were physician-determined relapses. Infections were the next most common events requiring hospitalization.
The overall annualized hospitalization rate was 0.26 in the eculizumab group and 0.78 in the placebo group. The difference between groups was statistically significant. In addition, the annualized relapse-related hospitalization rate was lower in the eculizumab group than in the placebo group (0.04 vs. 0.31, respectively).
The annualized relapse-related use of intravenous methylprednisolone for the eculizumab and placebo groups were 0.07 and 0.42, respectively; for use of plasma exchange, 0.02 and 0.19; and for use of high-dose oral corticosteroids, 0.04 and 0.11. The differences between groups in use of intravenous methylprednisolone and plasma exchange were statistically significant.
Alexion Pharmaceuticals, which markets eculizumab, sponsored the study. Dr. Wingerchuk received grants from Alexion during the study. He also received personal fees from Biogen, BrainStorm Therapeutics, Celgene, MedImmune, Novartis, and ONO Pharmaceutical.
SOURCE: Kim H et al. ACTRIMS 2020. Abstract P197.
REPORTING FROM ACTRIMS FORUM 2020
Serum NfL levels may predict 10-year deep gray matter volumes
WEST PALM BEACH, FLA. – , according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Researchers have begun to study longitudinal changes in serum NfL levels as a way to monitor axonal damage in patients with MS and see how they relate to other measures of neuronal loss, such as brain atrophy, and clinical outcomes over the long-term. “Deep gray matter volumes have been shown to correlate with neurological outcomes in MS patients. In particular, thalamic volume has been shown to correlate with measures of cognitive processing speed, such as the Symbol Digit Modalities Test,” said senior author Tanuja Chitnis, MD, professor of neurology at Harvard Medical School in Boston.
She and her colleagues sought to determine whether annual serum NfL measures could predict 10-year deep gray matter atrophy measured by volumetric MRI in patients with MS. They examined patients who were enrolled in the Comprehensive Longitudinal Investigations in MS at Brigham and Women’s Hospital (CLIMB) study. Eligible participants were enrolled within 5 years of disease onset and had had annual blood samples drawn for as long as 10 years. In all, 122 patients met these criteria. The investigators measured serum NfL and compared it against deep gray matter volume in the thalamus, caudate, putamen, and globus pallidus from high-resolution 3-T MRI scans taken at year 10. Dr. Chitnis and colleagues assessed correlations between averaged annual NfL and 10-year MRI outcomes using univariate and multivariate linear regression models.
About 96% of participants were white, and about 2% were black. Approximately 73% of participants were female. Average age at the first symptom was 36 years, and average age at the first sample collection was 38 years.
The investigators found several negative associations between averaged NfL values and various MRI volumetric outcomes. Averaged annual serum NfL levels for the first 5 years were significantly and negatively associated with 10-year thalamic volumes in the unadjusted analysis. A 1-pg/mL increase in the average sNfL value was associated with a decrease of 0.0000272 cm3 in thalamic volume. The association remained significant in an analysis adjusted for age, sex, and disease duration. In this analysis, a 1-pg/mL increase in the average sNfL value was associated with a decrease of 0.0000259 cm3 in thalamic volume. Analyzing serum NfL levels beyond year 5 did not reveal a stronger association. Serum NfL levels during the first 5 years accounted for about 24% of the variance in 10-year thalamic volumes. Dr. Chitnis and colleagues found similar statistically significant associations between serum NfL levels and caudate, putamen, and globus pallidus volumes. “Therefore, early serum NfL levels contribute to the identification of patients who may require highly effective therapies,” she said.
“We will continue to validate these results. As well, we are exploring other early biomarkers that increase predictive power of long-term outcomes in MS, with the goal of identifying patients most appropriate for high-efficacy treatments.”
The study was supported by funds from the U.S. Department of Defense, Novartis, and the Swiss National Research Foundation. Dr. Chitnis has received personal compensation for consulting and advisory board membership from Biogen, Merck Serono, Novartis, and Sanofi.
SOURCE: Lokhande H et al. ACTRIMS Forum 2020, Abstract P018.
WEST PALM BEACH, FLA. – , according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Researchers have begun to study longitudinal changes in serum NfL levels as a way to monitor axonal damage in patients with MS and see how they relate to other measures of neuronal loss, such as brain atrophy, and clinical outcomes over the long-term. “Deep gray matter volumes have been shown to correlate with neurological outcomes in MS patients. In particular, thalamic volume has been shown to correlate with measures of cognitive processing speed, such as the Symbol Digit Modalities Test,” said senior author Tanuja Chitnis, MD, professor of neurology at Harvard Medical School in Boston.
She and her colleagues sought to determine whether annual serum NfL measures could predict 10-year deep gray matter atrophy measured by volumetric MRI in patients with MS. They examined patients who were enrolled in the Comprehensive Longitudinal Investigations in MS at Brigham and Women’s Hospital (CLIMB) study. Eligible participants were enrolled within 5 years of disease onset and had had annual blood samples drawn for as long as 10 years. In all, 122 patients met these criteria. The investigators measured serum NfL and compared it against deep gray matter volume in the thalamus, caudate, putamen, and globus pallidus from high-resolution 3-T MRI scans taken at year 10. Dr. Chitnis and colleagues assessed correlations between averaged annual NfL and 10-year MRI outcomes using univariate and multivariate linear regression models.
About 96% of participants were white, and about 2% were black. Approximately 73% of participants were female. Average age at the first symptom was 36 years, and average age at the first sample collection was 38 years.
The investigators found several negative associations between averaged NfL values and various MRI volumetric outcomes. Averaged annual serum NfL levels for the first 5 years were significantly and negatively associated with 10-year thalamic volumes in the unadjusted analysis. A 1-pg/mL increase in the average sNfL value was associated with a decrease of 0.0000272 cm3 in thalamic volume. The association remained significant in an analysis adjusted for age, sex, and disease duration. In this analysis, a 1-pg/mL increase in the average sNfL value was associated with a decrease of 0.0000259 cm3 in thalamic volume. Analyzing serum NfL levels beyond year 5 did not reveal a stronger association. Serum NfL levels during the first 5 years accounted for about 24% of the variance in 10-year thalamic volumes. Dr. Chitnis and colleagues found similar statistically significant associations between serum NfL levels and caudate, putamen, and globus pallidus volumes. “Therefore, early serum NfL levels contribute to the identification of patients who may require highly effective therapies,” she said.
“We will continue to validate these results. As well, we are exploring other early biomarkers that increase predictive power of long-term outcomes in MS, with the goal of identifying patients most appropriate for high-efficacy treatments.”
The study was supported by funds from the U.S. Department of Defense, Novartis, and the Swiss National Research Foundation. Dr. Chitnis has received personal compensation for consulting and advisory board membership from Biogen, Merck Serono, Novartis, and Sanofi.
SOURCE: Lokhande H et al. ACTRIMS Forum 2020, Abstract P018.
WEST PALM BEACH, FLA. – , according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Researchers have begun to study longitudinal changes in serum NfL levels as a way to monitor axonal damage in patients with MS and see how they relate to other measures of neuronal loss, such as brain atrophy, and clinical outcomes over the long-term. “Deep gray matter volumes have been shown to correlate with neurological outcomes in MS patients. In particular, thalamic volume has been shown to correlate with measures of cognitive processing speed, such as the Symbol Digit Modalities Test,” said senior author Tanuja Chitnis, MD, professor of neurology at Harvard Medical School in Boston.
She and her colleagues sought to determine whether annual serum NfL measures could predict 10-year deep gray matter atrophy measured by volumetric MRI in patients with MS. They examined patients who were enrolled in the Comprehensive Longitudinal Investigations in MS at Brigham and Women’s Hospital (CLIMB) study. Eligible participants were enrolled within 5 years of disease onset and had had annual blood samples drawn for as long as 10 years. In all, 122 patients met these criteria. The investigators measured serum NfL and compared it against deep gray matter volume in the thalamus, caudate, putamen, and globus pallidus from high-resolution 3-T MRI scans taken at year 10. Dr. Chitnis and colleagues assessed correlations between averaged annual NfL and 10-year MRI outcomes using univariate and multivariate linear regression models.
About 96% of participants were white, and about 2% were black. Approximately 73% of participants were female. Average age at the first symptom was 36 years, and average age at the first sample collection was 38 years.
The investigators found several negative associations between averaged NfL values and various MRI volumetric outcomes. Averaged annual serum NfL levels for the first 5 years were significantly and negatively associated with 10-year thalamic volumes in the unadjusted analysis. A 1-pg/mL increase in the average sNfL value was associated with a decrease of 0.0000272 cm3 in thalamic volume. The association remained significant in an analysis adjusted for age, sex, and disease duration. In this analysis, a 1-pg/mL increase in the average sNfL value was associated with a decrease of 0.0000259 cm3 in thalamic volume. Analyzing serum NfL levels beyond year 5 did not reveal a stronger association. Serum NfL levels during the first 5 years accounted for about 24% of the variance in 10-year thalamic volumes. Dr. Chitnis and colleagues found similar statistically significant associations between serum NfL levels and caudate, putamen, and globus pallidus volumes. “Therefore, early serum NfL levels contribute to the identification of patients who may require highly effective therapies,” she said.
“We will continue to validate these results. As well, we are exploring other early biomarkers that increase predictive power of long-term outcomes in MS, with the goal of identifying patients most appropriate for high-efficacy treatments.”
The study was supported by funds from the U.S. Department of Defense, Novartis, and the Swiss National Research Foundation. Dr. Chitnis has received personal compensation for consulting and advisory board membership from Biogen, Merck Serono, Novartis, and Sanofi.
SOURCE: Lokhande H et al. ACTRIMS Forum 2020, Abstract P018.
REPORTING FROM ACTRIMS FORUM 2020
Key differences found between pediatric- and adult-onset MS
WEST PALM BEACH, FLA. – , according to data presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Among patients with POMS, researchers also have observed an association between fatigue and mood disorders on one hand and DMT choice on the other hand. “These findings confirm the unique features of POMS and suggest that DMT choice in POMS and AOMS may influence the frequency of fatigue and mood disorders,” said Mary Rensel, MD, staff neurologist in neuroimmunology at Cleveland Clinic’s Mellen Center for MS Treatment and Research, and colleagues.
POMS is defined as MS onset before age 18, and the disease characteristics of POMS and AOMS are distinct. The former diagnosis is rare, which has limited the amount of data collected on POMS to date.
MS Partners Advancing Technology and Health Solutions (MS-PATHS), sponsored by Biogen, is a multicenter initiative in which researchers collect MS performance measures longitudinally at each patient visit. MS-PATHS data include sociodemographic information, patient-reported outcomes (PROs), functional outcomes (FOs), MS phenotype, and DMT. Using MS-PATHS data, Dr. Rensel and colleagues sought to determine differences in sociodemographics, MS phenotype, PRO, FO, and DMT among patients with POMS and between patients with POMS and those with AOMS.
The investigators analyzed data cut 9 of the MS-PATHS database for their study. They included 637 participants with POMS and matched them with patients with AOMS, based on disease duration, in a 1:5 ratio. Dr. Rensel and colleagues categorized DMTs as high, mid, or low efficacy. They calculated descriptive statistics to characterize the study population. In addition, they compared MS FOs and PROs in the matched cohort using the Wilcoxon rank-sum test. Finally, linear regression analysis allowed the investigators to identify differences in the data set, while adjusting for important covariates.
The matched cohort included 5,857 patients with AOMS and 600 patients with POMS. The patients with AOMS had an average age of 49.8 years. About 87.5% of these patients were white, and 73.5% were female. The POMS patients had an average age of 31.49 years. Overall, 76.7% of these patients were white, and 73.2% were female. Dr. Rensel and colleagues found significant differences between the two groups in age at encounter, disease duration, race, insurance, Patient Determined Disease Steps (PDDS), education, employment, FOs, PROs, and DMT.
Patients with POMS used high-efficacy DMT more frequently than those with AOMS. The rate of depression was similar between patients with AOMS and those with POMS. Depression, anxiety, and fatigue were associated with DMT potency in AOMS, and anxiety and fatigue were associated with DMT groups in POMS.
Racial differences between POMS and AOMS have been reported previously, said Dr. Rensel. First-generation immigrant children have an increased risk of POMS, compared with other children. “In our data set, we had more Asians, more blacks, and fewer Caucasians in the POMS group,” said Dr. Rensel. People from a socioeconomically challenged environment have an increased risk of POMS, and this observation may explain the difference in insurance coverage between the POMS and AOMS groups, she added. Socioeconomic challenges also may explain the difference in the rate of higher education between the two groups.
“Why were the POMS cases associated with higher-efficacy DMT when only one oral MS DMT is [Food and Drug Administration]-approved for POMS?” Dr. Rensel asked. “This is likely due to the fact that POMS cases tend to have higher disease activity with more relapses and more brain lesions, leading to the choice of higher efficacy DMTs that are currently not FDA-approved for POMS.”
These data “may help [clinicians] caring for kids and teens, especially non-Caucasian [patients], to consider MS on the differential diagnosis,” Dr. Rensel added. “Mood disorders in POMS were as common as mood disorders in AOMS, so these should be screened for in this POMS population.”
Dr. Rensel has received funding for consulting, research, or patient education from Biogen, Genentech, Genzyme, Medimmune, MSAA, NMSS, Novartis, TSerono, and Teva.
SOURCE: Rensel M et al. ACTRIMS Forum 2020, Abstract P042.
WEST PALM BEACH, FLA. – , according to data presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Among patients with POMS, researchers also have observed an association between fatigue and mood disorders on one hand and DMT choice on the other hand. “These findings confirm the unique features of POMS and suggest that DMT choice in POMS and AOMS may influence the frequency of fatigue and mood disorders,” said Mary Rensel, MD, staff neurologist in neuroimmunology at Cleveland Clinic’s Mellen Center for MS Treatment and Research, and colleagues.
POMS is defined as MS onset before age 18, and the disease characteristics of POMS and AOMS are distinct. The former diagnosis is rare, which has limited the amount of data collected on POMS to date.
MS Partners Advancing Technology and Health Solutions (MS-PATHS), sponsored by Biogen, is a multicenter initiative in which researchers collect MS performance measures longitudinally at each patient visit. MS-PATHS data include sociodemographic information, patient-reported outcomes (PROs), functional outcomes (FOs), MS phenotype, and DMT. Using MS-PATHS data, Dr. Rensel and colleagues sought to determine differences in sociodemographics, MS phenotype, PRO, FO, and DMT among patients with POMS and between patients with POMS and those with AOMS.
The investigators analyzed data cut 9 of the MS-PATHS database for their study. They included 637 participants with POMS and matched them with patients with AOMS, based on disease duration, in a 1:5 ratio. Dr. Rensel and colleagues categorized DMTs as high, mid, or low efficacy. They calculated descriptive statistics to characterize the study population. In addition, they compared MS FOs and PROs in the matched cohort using the Wilcoxon rank-sum test. Finally, linear regression analysis allowed the investigators to identify differences in the data set, while adjusting for important covariates.
The matched cohort included 5,857 patients with AOMS and 600 patients with POMS. The patients with AOMS had an average age of 49.8 years. About 87.5% of these patients were white, and 73.5% were female. The POMS patients had an average age of 31.49 years. Overall, 76.7% of these patients were white, and 73.2% were female. Dr. Rensel and colleagues found significant differences between the two groups in age at encounter, disease duration, race, insurance, Patient Determined Disease Steps (PDDS), education, employment, FOs, PROs, and DMT.
Patients with POMS used high-efficacy DMT more frequently than those with AOMS. The rate of depression was similar between patients with AOMS and those with POMS. Depression, anxiety, and fatigue were associated with DMT potency in AOMS, and anxiety and fatigue were associated with DMT groups in POMS.
Racial differences between POMS and AOMS have been reported previously, said Dr. Rensel. First-generation immigrant children have an increased risk of POMS, compared with other children. “In our data set, we had more Asians, more blacks, and fewer Caucasians in the POMS group,” said Dr. Rensel. People from a socioeconomically challenged environment have an increased risk of POMS, and this observation may explain the difference in insurance coverage between the POMS and AOMS groups, she added. Socioeconomic challenges also may explain the difference in the rate of higher education between the two groups.
“Why were the POMS cases associated with higher-efficacy DMT when only one oral MS DMT is [Food and Drug Administration]-approved for POMS?” Dr. Rensel asked. “This is likely due to the fact that POMS cases tend to have higher disease activity with more relapses and more brain lesions, leading to the choice of higher efficacy DMTs that are currently not FDA-approved for POMS.”
These data “may help [clinicians] caring for kids and teens, especially non-Caucasian [patients], to consider MS on the differential diagnosis,” Dr. Rensel added. “Mood disorders in POMS were as common as mood disorders in AOMS, so these should be screened for in this POMS population.”
Dr. Rensel has received funding for consulting, research, or patient education from Biogen, Genentech, Genzyme, Medimmune, MSAA, NMSS, Novartis, TSerono, and Teva.
SOURCE: Rensel M et al. ACTRIMS Forum 2020, Abstract P042.
WEST PALM BEACH, FLA. – , according to data presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
Among patients with POMS, researchers also have observed an association between fatigue and mood disorders on one hand and DMT choice on the other hand. “These findings confirm the unique features of POMS and suggest that DMT choice in POMS and AOMS may influence the frequency of fatigue and mood disorders,” said Mary Rensel, MD, staff neurologist in neuroimmunology at Cleveland Clinic’s Mellen Center for MS Treatment and Research, and colleagues.
POMS is defined as MS onset before age 18, and the disease characteristics of POMS and AOMS are distinct. The former diagnosis is rare, which has limited the amount of data collected on POMS to date.
MS Partners Advancing Technology and Health Solutions (MS-PATHS), sponsored by Biogen, is a multicenter initiative in which researchers collect MS performance measures longitudinally at each patient visit. MS-PATHS data include sociodemographic information, patient-reported outcomes (PROs), functional outcomes (FOs), MS phenotype, and DMT. Using MS-PATHS data, Dr. Rensel and colleagues sought to determine differences in sociodemographics, MS phenotype, PRO, FO, and DMT among patients with POMS and between patients with POMS and those with AOMS.
The investigators analyzed data cut 9 of the MS-PATHS database for their study. They included 637 participants with POMS and matched them with patients with AOMS, based on disease duration, in a 1:5 ratio. Dr. Rensel and colleagues categorized DMTs as high, mid, or low efficacy. They calculated descriptive statistics to characterize the study population. In addition, they compared MS FOs and PROs in the matched cohort using the Wilcoxon rank-sum test. Finally, linear regression analysis allowed the investigators to identify differences in the data set, while adjusting for important covariates.
The matched cohort included 5,857 patients with AOMS and 600 patients with POMS. The patients with AOMS had an average age of 49.8 years. About 87.5% of these patients were white, and 73.5% were female. The POMS patients had an average age of 31.49 years. Overall, 76.7% of these patients were white, and 73.2% were female. Dr. Rensel and colleagues found significant differences between the two groups in age at encounter, disease duration, race, insurance, Patient Determined Disease Steps (PDDS), education, employment, FOs, PROs, and DMT.
Patients with POMS used high-efficacy DMT more frequently than those with AOMS. The rate of depression was similar between patients with AOMS and those with POMS. Depression, anxiety, and fatigue were associated with DMT potency in AOMS, and anxiety and fatigue were associated with DMT groups in POMS.
Racial differences between POMS and AOMS have been reported previously, said Dr. Rensel. First-generation immigrant children have an increased risk of POMS, compared with other children. “In our data set, we had more Asians, more blacks, and fewer Caucasians in the POMS group,” said Dr. Rensel. People from a socioeconomically challenged environment have an increased risk of POMS, and this observation may explain the difference in insurance coverage between the POMS and AOMS groups, she added. Socioeconomic challenges also may explain the difference in the rate of higher education between the two groups.
“Why were the POMS cases associated with higher-efficacy DMT when only one oral MS DMT is [Food and Drug Administration]-approved for POMS?” Dr. Rensel asked. “This is likely due to the fact that POMS cases tend to have higher disease activity with more relapses and more brain lesions, leading to the choice of higher efficacy DMTs that are currently not FDA-approved for POMS.”
These data “may help [clinicians] caring for kids and teens, especially non-Caucasian [patients], to consider MS on the differential diagnosis,” Dr. Rensel added. “Mood disorders in POMS were as common as mood disorders in AOMS, so these should be screened for in this POMS population.”
Dr. Rensel has received funding for consulting, research, or patient education from Biogen, Genentech, Genzyme, Medimmune, MSAA, NMSS, Novartis, TSerono, and Teva.
SOURCE: Rensel M et al. ACTRIMS Forum 2020, Abstract P042.
REPORTING FROM ACTRIMS FORUM 2020
OCT may help predict disease activity in CIS
WEST PALM BEACH, FLA. – according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The results suggest that optical coherence tomography (OCT) could support patient monitoring and the initiation of disease-modifying therapy.
“Treatment of early MS [multiple sclerosis] is crucial to prevent neuroaxonal damage and, thus, sustained disability,” said Hanna G. Zimmermann, PhD, a research associate at NeuroCure Clinical Research Center at Charité Universitätsmedizin in Berlin. The ability to identify patients at high risk of future disease activity shortly after disease onset could help optimize patient management and guide the initiation of disease-modifying therapy. Dr. Zimmermann and colleagues investigated whether retinal OCT could predict disease activity in patients with CIS.
The investigators included 97 patients (mean age, 33.6 years; 62.9% female) with CIS in a prospective, longitudinal cohort study. Diagnoses of CIS were based on the 2010 revisions to the McDonald criteria. Patients were enrolled from two German centers within 12 months after a first clinical event. The researchers performed a neurologic examination, cerebral MRI, and retinal OCT for each participant and followed the population for 729 days (median, 664 days).
The primary OCT predictor was ganglion cell and inner plexiform (GCIP) layer thickness, because this parameter is stable and reliable for quantifying neuronal visual system damage in MS, said Dr. Zimmermann. Secondary OCT predictors were peripapillary retinal nerve fiber layer (pRNFL) thickness and inner nuclear layer (INL) thickness. The investigators only included eyes without a history of optic neuritis in the analysis.
The study’s primary outcome was failing the no evidence of disease activity (NEDA-3) criteria (no relapses, no disability progression, and no MRI activity). The secondary outcomes were MS diagnosis (according to the 2010 McDonald criteria) and worsening of disability.
At baseline, Dr. Zimmerman and colleagues found no differences in thickness of GCIP and pRNFL between patients and matched healthy controls. In all, 58 patients (59%) failed NEDA-3 criteria during follow-up. When Dr. Zimmermann and colleagues conducted Kaplan-Meier analysis, they found that patients with thinner GCIP thickness had a significantly higher risk of failing NEDA-3 criteria (thinnest vs. thickest tertile: hazard ratio, 3.33). A follow-up diagnosis of MS also was significantly more likely among patients with low GCIP thickness (thinnest vs. thickest tertile: HR, 4.05).
In addition, low pRNFL thickness indicated an increased risk of not meeting NEDA-3 criteria (thinnest vs. thickest tertile: HR, 2.46). However, neither INL thickness nor T2-weighted lesion count were associated with failing NEDA-3 criteria. Also, none of the OCT parameters were associated with future disability worsening.
Among the study’s limitations are its small sample size, the relatively short observation time, and the heterogeneity of patients between the two centers, which used different study protocols, said Dr. Zimmermann.
“OCT-assessed GCIP is promising for the early appraisal of future disease activity and might thus be helpful for risk-adjusted patient participation in clinical research,” she said. “It might also be helpful for clinicians for identifying CIS patients with worse prognosis and planning the care.” Dr. Zimmermann and colleagues plan to use advanced imaging techniques in future studies to understand the mechanisms behind the associations they identified. They hope to confirm their findings in a larger cohort and examine whether OCT can predict clinical outcomes such as relapses, disability worsening, and the extent of disease activity.
Dr. Zimmermann had no relevant disclosures and did not report a source of funding for the study.
SOURCE: Zimmermann HG et al. ACTRIMS Forum 2020, Abstract.
WEST PALM BEACH, FLA. – according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The results suggest that optical coherence tomography (OCT) could support patient monitoring and the initiation of disease-modifying therapy.
“Treatment of early MS [multiple sclerosis] is crucial to prevent neuroaxonal damage and, thus, sustained disability,” said Hanna G. Zimmermann, PhD, a research associate at NeuroCure Clinical Research Center at Charité Universitätsmedizin in Berlin. The ability to identify patients at high risk of future disease activity shortly after disease onset could help optimize patient management and guide the initiation of disease-modifying therapy. Dr. Zimmermann and colleagues investigated whether retinal OCT could predict disease activity in patients with CIS.
The investigators included 97 patients (mean age, 33.6 years; 62.9% female) with CIS in a prospective, longitudinal cohort study. Diagnoses of CIS were based on the 2010 revisions to the McDonald criteria. Patients were enrolled from two German centers within 12 months after a first clinical event. The researchers performed a neurologic examination, cerebral MRI, and retinal OCT for each participant and followed the population for 729 days (median, 664 days).
The primary OCT predictor was ganglion cell and inner plexiform (GCIP) layer thickness, because this parameter is stable and reliable for quantifying neuronal visual system damage in MS, said Dr. Zimmermann. Secondary OCT predictors were peripapillary retinal nerve fiber layer (pRNFL) thickness and inner nuclear layer (INL) thickness. The investigators only included eyes without a history of optic neuritis in the analysis.
The study’s primary outcome was failing the no evidence of disease activity (NEDA-3) criteria (no relapses, no disability progression, and no MRI activity). The secondary outcomes were MS diagnosis (according to the 2010 McDonald criteria) and worsening of disability.
At baseline, Dr. Zimmerman and colleagues found no differences in thickness of GCIP and pRNFL between patients and matched healthy controls. In all, 58 patients (59%) failed NEDA-3 criteria during follow-up. When Dr. Zimmermann and colleagues conducted Kaplan-Meier analysis, they found that patients with thinner GCIP thickness had a significantly higher risk of failing NEDA-3 criteria (thinnest vs. thickest tertile: hazard ratio, 3.33). A follow-up diagnosis of MS also was significantly more likely among patients with low GCIP thickness (thinnest vs. thickest tertile: HR, 4.05).
In addition, low pRNFL thickness indicated an increased risk of not meeting NEDA-3 criteria (thinnest vs. thickest tertile: HR, 2.46). However, neither INL thickness nor T2-weighted lesion count were associated with failing NEDA-3 criteria. Also, none of the OCT parameters were associated with future disability worsening.
Among the study’s limitations are its small sample size, the relatively short observation time, and the heterogeneity of patients between the two centers, which used different study protocols, said Dr. Zimmermann.
“OCT-assessed GCIP is promising for the early appraisal of future disease activity and might thus be helpful for risk-adjusted patient participation in clinical research,” she said. “It might also be helpful for clinicians for identifying CIS patients with worse prognosis and planning the care.” Dr. Zimmermann and colleagues plan to use advanced imaging techniques in future studies to understand the mechanisms behind the associations they identified. They hope to confirm their findings in a larger cohort and examine whether OCT can predict clinical outcomes such as relapses, disability worsening, and the extent of disease activity.
Dr. Zimmermann had no relevant disclosures and did not report a source of funding for the study.
SOURCE: Zimmermann HG et al. ACTRIMS Forum 2020, Abstract.
WEST PALM BEACH, FLA. – according to research presented at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. The results suggest that optical coherence tomography (OCT) could support patient monitoring and the initiation of disease-modifying therapy.
“Treatment of early MS [multiple sclerosis] is crucial to prevent neuroaxonal damage and, thus, sustained disability,” said Hanna G. Zimmermann, PhD, a research associate at NeuroCure Clinical Research Center at Charité Universitätsmedizin in Berlin. The ability to identify patients at high risk of future disease activity shortly after disease onset could help optimize patient management and guide the initiation of disease-modifying therapy. Dr. Zimmermann and colleagues investigated whether retinal OCT could predict disease activity in patients with CIS.
The investigators included 97 patients (mean age, 33.6 years; 62.9% female) with CIS in a prospective, longitudinal cohort study. Diagnoses of CIS were based on the 2010 revisions to the McDonald criteria. Patients were enrolled from two German centers within 12 months after a first clinical event. The researchers performed a neurologic examination, cerebral MRI, and retinal OCT for each participant and followed the population for 729 days (median, 664 days).
The primary OCT predictor was ganglion cell and inner plexiform (GCIP) layer thickness, because this parameter is stable and reliable for quantifying neuronal visual system damage in MS, said Dr. Zimmermann. Secondary OCT predictors were peripapillary retinal nerve fiber layer (pRNFL) thickness and inner nuclear layer (INL) thickness. The investigators only included eyes without a history of optic neuritis in the analysis.
The study’s primary outcome was failing the no evidence of disease activity (NEDA-3) criteria (no relapses, no disability progression, and no MRI activity). The secondary outcomes were MS diagnosis (according to the 2010 McDonald criteria) and worsening of disability.
At baseline, Dr. Zimmerman and colleagues found no differences in thickness of GCIP and pRNFL between patients and matched healthy controls. In all, 58 patients (59%) failed NEDA-3 criteria during follow-up. When Dr. Zimmermann and colleagues conducted Kaplan-Meier analysis, they found that patients with thinner GCIP thickness had a significantly higher risk of failing NEDA-3 criteria (thinnest vs. thickest tertile: hazard ratio, 3.33). A follow-up diagnosis of MS also was significantly more likely among patients with low GCIP thickness (thinnest vs. thickest tertile: HR, 4.05).
In addition, low pRNFL thickness indicated an increased risk of not meeting NEDA-3 criteria (thinnest vs. thickest tertile: HR, 2.46). However, neither INL thickness nor T2-weighted lesion count were associated with failing NEDA-3 criteria. Also, none of the OCT parameters were associated with future disability worsening.
Among the study’s limitations are its small sample size, the relatively short observation time, and the heterogeneity of patients between the two centers, which used different study protocols, said Dr. Zimmermann.
“OCT-assessed GCIP is promising for the early appraisal of future disease activity and might thus be helpful for risk-adjusted patient participation in clinical research,” she said. “It might also be helpful for clinicians for identifying CIS patients with worse prognosis and planning the care.” Dr. Zimmermann and colleagues plan to use advanced imaging techniques in future studies to understand the mechanisms behind the associations they identified. They hope to confirm their findings in a larger cohort and examine whether OCT can predict clinical outcomes such as relapses, disability worsening, and the extent of disease activity.
Dr. Zimmermann had no relevant disclosures and did not report a source of funding for the study.
SOURCE: Zimmermann HG et al. ACTRIMS Forum 2020, Abstract.
REPORTING FROM ACTRIMS FORUM 2020
Antiepileptic drugs may not independently impair cognition
according to research published online ahead of print Feb. 3 in Neurology. Optimizing AED therapy to reduce or prevent seizures is thus unlikely to affect cognition, according to the investigators.
Patients who take AEDs commonly report cognitive problems, but investigations into the cognitive effects of AEDs have yielded inconsistent results. “We were also interested in this association, as we often treat complex patients taking multiple or high-dose AEDs, and our patients often report cognitive dysfunction,” said Emma Foster, MBBS, an epilepsy fellow at Alfred Health and the Royal Melbourne Hospital in Victoria, Australia. “We were particularly interested to examine how much AEDs affect cognition relative to other factors. We commonly see patients in our tertiary epilepsy care unit who have had severe epilepsy for a long time or who have psychiatric disorders, and these factors may also contribute to cognitive dysfunction.”
Researchers analyzed patients admitted for video EEG monitoring
For their study, Dr. Foster and colleagues prospectively enrolled patients admitted to the Royal Melbourne Hospital’s video EEG monitoring unit between January 2009 and December 2016. Patients were included in the study if they were age 18 years or older, had been admitted for diagnostic or surgical evaluation, and had complete data for the relevant variables. Patients were prescribed AED monotherapy or polytherapy.
The researchers based epilepsy diagnoses on the 2014 International League Against Epilepsy criteria. Diagnoses of psychogenic nonepileptic seizures (PNES) were based on a consensus of epileptologists at weekly multidisciplinary clinical meetings, which was supported by evaluation of all available data. Some patients received a diagnosis of comorbid epilepsy and PNES. If data were insufficient to support a diagnosis of epilepsy or PNES, the admission was considered nondiagnostic.
All participants underwent neuropsychologic and neuropsychiatric screening. Researchers assessed patients’ objective, global cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), a validated instrument. Patients responded to the Quality of Life in Epilepsy inventory (QOLIE-89) to provide a measure of subjective cognitive function. They also responded to the Hospital Anxiety and Depression Scale (HADS) to screen for mood disorders.
Dr. Foster and colleagues measured seizure frequency through patient self-report. Patients averaged their seizure frequency during the 12-month period before admission to the video EEG unit. They categorized it according to a 12-point system in which 0 denotes patients who are seizure-free and not taking AEDs and 12 denotes patients in status epilepticus. Patients with PNES used the same scale to report event frequency, although the system was not designed for this purpose.
Almost half of patients were prescribed polypharmacy
The researchers included 331 patients in their analysis. The population’s mean age was 39.3 years, and about 62% of patients were female. Approximately 47% of patients had epilepsy, 25.7% had PNES, 6.6% had comorbid epilepsy and PNES, and 20.5% had a nondiagnostic outcome. Among patients with epilepsy, most (54.5%) had temporal lobe epilepsy, followed by extratemporal focal epilepsy (32.1%) and generalized epilepsy (13.5%). The mean number of AEDs prescribed on admission was 1.6, and mean seizure or event frequency score was 7.2, which indicated 1-3 seizures per month. Mean HADS depression score was within the normal range (5.7), and mean HADS anxiety score was in the borderline range (8.2).
Approximately 45% of patients were prescribed AED polypharmacy on admission, 25.1% were prescribed AED monotherapy, and 29.9% were prescribed no AED. Levetiracetam, valproate, and carbamazepine were the most frequently prescribed AEDs. Most patients with epilepsy (73.1%) were on polypharmacy, compared with 17.6% of patients with PNES, 63.6% of patients with epilepsy and PNES, and 8.8% of nondiagnostic patients.
Older age and greater seizure frequency predicted impaired objective cognitive function. Comorbid epilepsy and PNES appeared to predict impaired objective cognitive function as well, but the data were inconclusive. No AED was a significant predictor of objective cognitive function. Higher depression and anxiety scores and greater seizure frequency predicted impaired subjective cognitive function. No AED predicted subjective cognitive function.
Future studies could address particular cognitive domains
Previous studies have suggested that treatment with topiramate predicts objective or subjective cognitive function, but Dr. Foster and colleagues did not observe this result. The current findings suggest that topiramate may have a less significant effect on cognition than the literature suggests, they wrote. In addition, more evidence is needed to fully understand the effects of clobazam, valproate, phenytoin, and gabapentin because the analysis was underpowered for these drugs.
Although NUCOG assesses global cognitive function reliably, its ability to measure particular cognitive subdomains is limited. “We aim to conduct future research investigating the complex associations between different cognitive functions, including processing speed, and specific AEDs in this heterogeneous population,” said Dr. Foster.
Despite the study’s large sample size, the researchers could not explore potential interactions between various predictor variables. “Epilepsy may interact with the aging process or with other medical conditions associated with aging, such as hypertension and diabetes, and this may increase the risk of cognitive decline,” said Dr. Foster. “Older age may also be associated with reduced capacity to metabolize drugs, increased sensitivity to the cognitive and neurological effects of drugs, less cognitive reserve, and increased likelihood of taking multiple medications, which, along with AEDs, may exert a cognitive effect.”
The current findings may reduce concerns about the effects of AEDs on cognitive function and encourage neurologists to pursue the proper dosing for optimal seizure control, wrote the authors. “However, it is possible that some individuals may be more susceptible than others to AED-related cognitive dysfunction,” said Dr. Foster. “We do not have a robust way to predict who these patients will be, and it is still good practice to make patients aware that some people experience adverse cognitive effects from AEDs. However, it needs to be emphasized that it is unlikely to be the sole reason for their cognitive impairment. Other issues, such as poor seizure control or unrecognized or undertreated mood disorders, are even more important factors for impaired cognition.”
Patients who report cognitive problems should be screened for mood disorders, Dr. Foster continued. “It would also be important to consider whether the patients’ cognitive complaints arise from subtle clinical or subclinical seizure activity and subsequent postictal periods. To investigate this [question] further, clinicians may arrange for prolonged EEG monitoring. This [monitoring] could be done in an ambulatory setting or during an inpatient admission.”
The study was conducted without external funding. Dr. Foster and other investigators reported research funding from professional associations and pharmaceutical companies that was unrelated to the study.
SOURCE: Foster E et al. Neurology. 2020 Feb 3. doi: 10.1212/WNL.0000000000009061.
according to research published online ahead of print Feb. 3 in Neurology. Optimizing AED therapy to reduce or prevent seizures is thus unlikely to affect cognition, according to the investigators.
Patients who take AEDs commonly report cognitive problems, but investigations into the cognitive effects of AEDs have yielded inconsistent results. “We were also interested in this association, as we often treat complex patients taking multiple or high-dose AEDs, and our patients often report cognitive dysfunction,” said Emma Foster, MBBS, an epilepsy fellow at Alfred Health and the Royal Melbourne Hospital in Victoria, Australia. “We were particularly interested to examine how much AEDs affect cognition relative to other factors. We commonly see patients in our tertiary epilepsy care unit who have had severe epilepsy for a long time or who have psychiatric disorders, and these factors may also contribute to cognitive dysfunction.”
Researchers analyzed patients admitted for video EEG monitoring
For their study, Dr. Foster and colleagues prospectively enrolled patients admitted to the Royal Melbourne Hospital’s video EEG monitoring unit between January 2009 and December 2016. Patients were included in the study if they were age 18 years or older, had been admitted for diagnostic or surgical evaluation, and had complete data for the relevant variables. Patients were prescribed AED monotherapy or polytherapy.
The researchers based epilepsy diagnoses on the 2014 International League Against Epilepsy criteria. Diagnoses of psychogenic nonepileptic seizures (PNES) were based on a consensus of epileptologists at weekly multidisciplinary clinical meetings, which was supported by evaluation of all available data. Some patients received a diagnosis of comorbid epilepsy and PNES. If data were insufficient to support a diagnosis of epilepsy or PNES, the admission was considered nondiagnostic.
All participants underwent neuropsychologic and neuropsychiatric screening. Researchers assessed patients’ objective, global cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), a validated instrument. Patients responded to the Quality of Life in Epilepsy inventory (QOLIE-89) to provide a measure of subjective cognitive function. They also responded to the Hospital Anxiety and Depression Scale (HADS) to screen for mood disorders.
Dr. Foster and colleagues measured seizure frequency through patient self-report. Patients averaged their seizure frequency during the 12-month period before admission to the video EEG unit. They categorized it according to a 12-point system in which 0 denotes patients who are seizure-free and not taking AEDs and 12 denotes patients in status epilepticus. Patients with PNES used the same scale to report event frequency, although the system was not designed for this purpose.
Almost half of patients were prescribed polypharmacy
The researchers included 331 patients in their analysis. The population’s mean age was 39.3 years, and about 62% of patients were female. Approximately 47% of patients had epilepsy, 25.7% had PNES, 6.6% had comorbid epilepsy and PNES, and 20.5% had a nondiagnostic outcome. Among patients with epilepsy, most (54.5%) had temporal lobe epilepsy, followed by extratemporal focal epilepsy (32.1%) and generalized epilepsy (13.5%). The mean number of AEDs prescribed on admission was 1.6, and mean seizure or event frequency score was 7.2, which indicated 1-3 seizures per month. Mean HADS depression score was within the normal range (5.7), and mean HADS anxiety score was in the borderline range (8.2).
Approximately 45% of patients were prescribed AED polypharmacy on admission, 25.1% were prescribed AED monotherapy, and 29.9% were prescribed no AED. Levetiracetam, valproate, and carbamazepine were the most frequently prescribed AEDs. Most patients with epilepsy (73.1%) were on polypharmacy, compared with 17.6% of patients with PNES, 63.6% of patients with epilepsy and PNES, and 8.8% of nondiagnostic patients.
Older age and greater seizure frequency predicted impaired objective cognitive function. Comorbid epilepsy and PNES appeared to predict impaired objective cognitive function as well, but the data were inconclusive. No AED was a significant predictor of objective cognitive function. Higher depression and anxiety scores and greater seizure frequency predicted impaired subjective cognitive function. No AED predicted subjective cognitive function.
Future studies could address particular cognitive domains
Previous studies have suggested that treatment with topiramate predicts objective or subjective cognitive function, but Dr. Foster and colleagues did not observe this result. The current findings suggest that topiramate may have a less significant effect on cognition than the literature suggests, they wrote. In addition, more evidence is needed to fully understand the effects of clobazam, valproate, phenytoin, and gabapentin because the analysis was underpowered for these drugs.
Although NUCOG assesses global cognitive function reliably, its ability to measure particular cognitive subdomains is limited. “We aim to conduct future research investigating the complex associations between different cognitive functions, including processing speed, and specific AEDs in this heterogeneous population,” said Dr. Foster.
Despite the study’s large sample size, the researchers could not explore potential interactions between various predictor variables. “Epilepsy may interact with the aging process or with other medical conditions associated with aging, such as hypertension and diabetes, and this may increase the risk of cognitive decline,” said Dr. Foster. “Older age may also be associated with reduced capacity to metabolize drugs, increased sensitivity to the cognitive and neurological effects of drugs, less cognitive reserve, and increased likelihood of taking multiple medications, which, along with AEDs, may exert a cognitive effect.”
The current findings may reduce concerns about the effects of AEDs on cognitive function and encourage neurologists to pursue the proper dosing for optimal seizure control, wrote the authors. “However, it is possible that some individuals may be more susceptible than others to AED-related cognitive dysfunction,” said Dr. Foster. “We do not have a robust way to predict who these patients will be, and it is still good practice to make patients aware that some people experience adverse cognitive effects from AEDs. However, it needs to be emphasized that it is unlikely to be the sole reason for their cognitive impairment. Other issues, such as poor seizure control or unrecognized or undertreated mood disorders, are even more important factors for impaired cognition.”
Patients who report cognitive problems should be screened for mood disorders, Dr. Foster continued. “It would also be important to consider whether the patients’ cognitive complaints arise from subtle clinical or subclinical seizure activity and subsequent postictal periods. To investigate this [question] further, clinicians may arrange for prolonged EEG monitoring. This [monitoring] could be done in an ambulatory setting or during an inpatient admission.”
The study was conducted without external funding. Dr. Foster and other investigators reported research funding from professional associations and pharmaceutical companies that was unrelated to the study.
SOURCE: Foster E et al. Neurology. 2020 Feb 3. doi: 10.1212/WNL.0000000000009061.
according to research published online ahead of print Feb. 3 in Neurology. Optimizing AED therapy to reduce or prevent seizures is thus unlikely to affect cognition, according to the investigators.
Patients who take AEDs commonly report cognitive problems, but investigations into the cognitive effects of AEDs have yielded inconsistent results. “We were also interested in this association, as we often treat complex patients taking multiple or high-dose AEDs, and our patients often report cognitive dysfunction,” said Emma Foster, MBBS, an epilepsy fellow at Alfred Health and the Royal Melbourne Hospital in Victoria, Australia. “We were particularly interested to examine how much AEDs affect cognition relative to other factors. We commonly see patients in our tertiary epilepsy care unit who have had severe epilepsy for a long time or who have psychiatric disorders, and these factors may also contribute to cognitive dysfunction.”
Researchers analyzed patients admitted for video EEG monitoring
For their study, Dr. Foster and colleagues prospectively enrolled patients admitted to the Royal Melbourne Hospital’s video EEG monitoring unit between January 2009 and December 2016. Patients were included in the study if they were age 18 years or older, had been admitted for diagnostic or surgical evaluation, and had complete data for the relevant variables. Patients were prescribed AED monotherapy or polytherapy.
The researchers based epilepsy diagnoses on the 2014 International League Against Epilepsy criteria. Diagnoses of psychogenic nonepileptic seizures (PNES) were based on a consensus of epileptologists at weekly multidisciplinary clinical meetings, which was supported by evaluation of all available data. Some patients received a diagnosis of comorbid epilepsy and PNES. If data were insufficient to support a diagnosis of epilepsy or PNES, the admission was considered nondiagnostic.
All participants underwent neuropsychologic and neuropsychiatric screening. Researchers assessed patients’ objective, global cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), a validated instrument. Patients responded to the Quality of Life in Epilepsy inventory (QOLIE-89) to provide a measure of subjective cognitive function. They also responded to the Hospital Anxiety and Depression Scale (HADS) to screen for mood disorders.
Dr. Foster and colleagues measured seizure frequency through patient self-report. Patients averaged their seizure frequency during the 12-month period before admission to the video EEG unit. They categorized it according to a 12-point system in which 0 denotes patients who are seizure-free and not taking AEDs and 12 denotes patients in status epilepticus. Patients with PNES used the same scale to report event frequency, although the system was not designed for this purpose.
Almost half of patients were prescribed polypharmacy
The researchers included 331 patients in their analysis. The population’s mean age was 39.3 years, and about 62% of patients were female. Approximately 47% of patients had epilepsy, 25.7% had PNES, 6.6% had comorbid epilepsy and PNES, and 20.5% had a nondiagnostic outcome. Among patients with epilepsy, most (54.5%) had temporal lobe epilepsy, followed by extratemporal focal epilepsy (32.1%) and generalized epilepsy (13.5%). The mean number of AEDs prescribed on admission was 1.6, and mean seizure or event frequency score was 7.2, which indicated 1-3 seizures per month. Mean HADS depression score was within the normal range (5.7), and mean HADS anxiety score was in the borderline range (8.2).
Approximately 45% of patients were prescribed AED polypharmacy on admission, 25.1% were prescribed AED monotherapy, and 29.9% were prescribed no AED. Levetiracetam, valproate, and carbamazepine were the most frequently prescribed AEDs. Most patients with epilepsy (73.1%) were on polypharmacy, compared with 17.6% of patients with PNES, 63.6% of patients with epilepsy and PNES, and 8.8% of nondiagnostic patients.
Older age and greater seizure frequency predicted impaired objective cognitive function. Comorbid epilepsy and PNES appeared to predict impaired objective cognitive function as well, but the data were inconclusive. No AED was a significant predictor of objective cognitive function. Higher depression and anxiety scores and greater seizure frequency predicted impaired subjective cognitive function. No AED predicted subjective cognitive function.
Future studies could address particular cognitive domains
Previous studies have suggested that treatment with topiramate predicts objective or subjective cognitive function, but Dr. Foster and colleagues did not observe this result. The current findings suggest that topiramate may have a less significant effect on cognition than the literature suggests, they wrote. In addition, more evidence is needed to fully understand the effects of clobazam, valproate, phenytoin, and gabapentin because the analysis was underpowered for these drugs.
Although NUCOG assesses global cognitive function reliably, its ability to measure particular cognitive subdomains is limited. “We aim to conduct future research investigating the complex associations between different cognitive functions, including processing speed, and specific AEDs in this heterogeneous population,” said Dr. Foster.
Despite the study’s large sample size, the researchers could not explore potential interactions between various predictor variables. “Epilepsy may interact with the aging process or with other medical conditions associated with aging, such as hypertension and diabetes, and this may increase the risk of cognitive decline,” said Dr. Foster. “Older age may also be associated with reduced capacity to metabolize drugs, increased sensitivity to the cognitive and neurological effects of drugs, less cognitive reserve, and increased likelihood of taking multiple medications, which, along with AEDs, may exert a cognitive effect.”
The current findings may reduce concerns about the effects of AEDs on cognitive function and encourage neurologists to pursue the proper dosing for optimal seizure control, wrote the authors. “However, it is possible that some individuals may be more susceptible than others to AED-related cognitive dysfunction,” said Dr. Foster. “We do not have a robust way to predict who these patients will be, and it is still good practice to make patients aware that some people experience adverse cognitive effects from AEDs. However, it needs to be emphasized that it is unlikely to be the sole reason for their cognitive impairment. Other issues, such as poor seizure control or unrecognized or undertreated mood disorders, are even more important factors for impaired cognition.”
Patients who report cognitive problems should be screened for mood disorders, Dr. Foster continued. “It would also be important to consider whether the patients’ cognitive complaints arise from subtle clinical or subclinical seizure activity and subsequent postictal periods. To investigate this [question] further, clinicians may arrange for prolonged EEG monitoring. This [monitoring] could be done in an ambulatory setting or during an inpatient admission.”
The study was conducted without external funding. Dr. Foster and other investigators reported research funding from professional associations and pharmaceutical companies that was unrelated to the study.
SOURCE: Foster E et al. Neurology. 2020 Feb 3. doi: 10.1212/WNL.0000000000009061.
FROM NEUROLOGY
AAN publishes guideline on the treatment of sleep problems in children with autism
The guideline was published online ahead of print Feb. 12 in Neurology.
“While up to 40% of children and teens in the general population will have sleep problems at some point during their childhood, such problems usually lessen with age,” lead author Ashura Williams Buckley, MD, director of the Sleep and Neurodevelopment Service at the National Institute of Mental Health in Bethesda, Md., said in a press release. “For children and teens with autism, sleep problems are more common and more likely to persist, resulting in poor health and poor quality of life. Some sleep problems may be directly related to autism, but others are not. Regardless, autism symptoms may make sleep problems worse.”
Few evidence-based treatments are available
Dr. Williams Buckley and colleagues developed the current guideline to evaluate which pharmacologic, behavioral, and complementary and alternative medicine (CAM) interventions improve bedtime resistance, sleep onset latency, sleep continuity, total sleep time, and daytime behavior in children and adolescents with ASD. The panel evaluated 900 abstracts of articles that had been included in systematic reviews, as well as 1,087 additional abstracts. One hundred thirty-nine articles were potentially relevant, 12 met criteria for data extraction, and eight were rated class III or higher and were included in the panel’s review.
The authors observed what they called a dearth of evidence-based treatments for sleep dysregulation in ASD. Evidence indicates that melatonin, with or without cognitive–behavioral therapy (CBT), improves several sleep outcomes, compared with placebo. “Evidence for other interventions is largely lacking,” wrote Dr. Williams Buckley and colleagues. They observed a lack of long-term safety data for melatonin in children, which they considered concerning, because melatonin affects the hypothalamic–gonadal axis and can potentially influence pubertal development.
Screening for comorbid conditions and concomitant medications
The guideline recommends that clinicians assess children with ASD and sleep disturbances for coexisting conditions and concomitant medications that could be contributing to these sleep disturbances. They should ensure that children receive appropriate treatment for coexisting conditions and adjust or discontinue potentially problematic medications appropriately, according to the guideline.
Furthermore, clinicians should counsel parents or guardians about behavioral strategies as a first-line treatment for improving sleep function. These strategies could be administered alone or with pharmacologic or neutraceutical approaches as needed, according to the authors. Suggested behavioral approaches include unmodified extinction (i.e., imposing a bedtime and ignoring a child’s protests), graduated extinction (i.e., ignoring protests for a specified period before responding), positive routines (i.e., establishing pre-bedtime calming rituals), and bedtime fading (i.e., putting a child to bed close to the time he or she begins to fall asleep).
If a child’s contributing coexisting conditions and medications have been addressed and behavioral strategies have not been helpful, clinicians should offer melatonin, according to the guideline. Because over-the-counter formulations contain variable concentrations of melatonin, clinicians should write a prescription for it or recommend high-purity pharmaceutical grade melatonin. The initial dose should be 1-3 mg/day at 60-30 minutes before bedtime. The dose can be titrated to 10 mg/day. Clinicians also should counsel children and their parents about potential adverse events of melatonin and the lack of long-term safety data, according to the guideline.
In addition, clinicians should advise children and parents that no evidence supports the routine use of weighted blankets or specialized mattress technology for improving sleep. Parents who ask about weighted blankets should be told that the reviewed trial reported no serious adverse events with this intervention, and that blankets could be a reasonable nonpharmacologic approach for some patients, according to the guideline.
Optimal outcome measures are undefined
Dr. Williams Buckley and colleagues also suggested areas for future research. Investigators have not yet defined optimal outcome measures (e.g., questionnaires, polysomnography, and actigraphy) that balance tolerability and accuracy, they wrote. Clinically important differences for most measures also have yet to be determined. Researchers should investigate whether long-term adverse events are associated with chronic melatonin use and study patients with ASD and comorbid mood disorders, wrote the authors. “Research tying the underlying neurobiology in early-life sleep disruption to behavior might help clinicians and researchers understand which treatments might work for which people with ASD,” they concluded.
The AAN supported the development of the guideline. Dr. Williams Buckley had no conflicts of interest. Six authors had conflicts of interest that the AAN deemed not significant enough to prevent their participation in the development of the guideline.
SOURCE: Williams Buckley A et al. Neurology. 2020;94:393-405. doi: 10.1212/WNL0000000000009033.
The guideline was published online ahead of print Feb. 12 in Neurology.
“While up to 40% of children and teens in the general population will have sleep problems at some point during their childhood, such problems usually lessen with age,” lead author Ashura Williams Buckley, MD, director of the Sleep and Neurodevelopment Service at the National Institute of Mental Health in Bethesda, Md., said in a press release. “For children and teens with autism, sleep problems are more common and more likely to persist, resulting in poor health and poor quality of life. Some sleep problems may be directly related to autism, but others are not. Regardless, autism symptoms may make sleep problems worse.”
Few evidence-based treatments are available
Dr. Williams Buckley and colleagues developed the current guideline to evaluate which pharmacologic, behavioral, and complementary and alternative medicine (CAM) interventions improve bedtime resistance, sleep onset latency, sleep continuity, total sleep time, and daytime behavior in children and adolescents with ASD. The panel evaluated 900 abstracts of articles that had been included in systematic reviews, as well as 1,087 additional abstracts. One hundred thirty-nine articles were potentially relevant, 12 met criteria for data extraction, and eight were rated class III or higher and were included in the panel’s review.
The authors observed what they called a dearth of evidence-based treatments for sleep dysregulation in ASD. Evidence indicates that melatonin, with or without cognitive–behavioral therapy (CBT), improves several sleep outcomes, compared with placebo. “Evidence for other interventions is largely lacking,” wrote Dr. Williams Buckley and colleagues. They observed a lack of long-term safety data for melatonin in children, which they considered concerning, because melatonin affects the hypothalamic–gonadal axis and can potentially influence pubertal development.
Screening for comorbid conditions and concomitant medications
The guideline recommends that clinicians assess children with ASD and sleep disturbances for coexisting conditions and concomitant medications that could be contributing to these sleep disturbances. They should ensure that children receive appropriate treatment for coexisting conditions and adjust or discontinue potentially problematic medications appropriately, according to the guideline.
Furthermore, clinicians should counsel parents or guardians about behavioral strategies as a first-line treatment for improving sleep function. These strategies could be administered alone or with pharmacologic or neutraceutical approaches as needed, according to the authors. Suggested behavioral approaches include unmodified extinction (i.e., imposing a bedtime and ignoring a child’s protests), graduated extinction (i.e., ignoring protests for a specified period before responding), positive routines (i.e., establishing pre-bedtime calming rituals), and bedtime fading (i.e., putting a child to bed close to the time he or she begins to fall asleep).
If a child’s contributing coexisting conditions and medications have been addressed and behavioral strategies have not been helpful, clinicians should offer melatonin, according to the guideline. Because over-the-counter formulations contain variable concentrations of melatonin, clinicians should write a prescription for it or recommend high-purity pharmaceutical grade melatonin. The initial dose should be 1-3 mg/day at 60-30 minutes before bedtime. The dose can be titrated to 10 mg/day. Clinicians also should counsel children and their parents about potential adverse events of melatonin and the lack of long-term safety data, according to the guideline.
In addition, clinicians should advise children and parents that no evidence supports the routine use of weighted blankets or specialized mattress technology for improving sleep. Parents who ask about weighted blankets should be told that the reviewed trial reported no serious adverse events with this intervention, and that blankets could be a reasonable nonpharmacologic approach for some patients, according to the guideline.
Optimal outcome measures are undefined
Dr. Williams Buckley and colleagues also suggested areas for future research. Investigators have not yet defined optimal outcome measures (e.g., questionnaires, polysomnography, and actigraphy) that balance tolerability and accuracy, they wrote. Clinically important differences for most measures also have yet to be determined. Researchers should investigate whether long-term adverse events are associated with chronic melatonin use and study patients with ASD and comorbid mood disorders, wrote the authors. “Research tying the underlying neurobiology in early-life sleep disruption to behavior might help clinicians and researchers understand which treatments might work for which people with ASD,” they concluded.
The AAN supported the development of the guideline. Dr. Williams Buckley had no conflicts of interest. Six authors had conflicts of interest that the AAN deemed not significant enough to prevent their participation in the development of the guideline.
SOURCE: Williams Buckley A et al. Neurology. 2020;94:393-405. doi: 10.1212/WNL0000000000009033.
The guideline was published online ahead of print Feb. 12 in Neurology.
“While up to 40% of children and teens in the general population will have sleep problems at some point during their childhood, such problems usually lessen with age,” lead author Ashura Williams Buckley, MD, director of the Sleep and Neurodevelopment Service at the National Institute of Mental Health in Bethesda, Md., said in a press release. “For children and teens with autism, sleep problems are more common and more likely to persist, resulting in poor health and poor quality of life. Some sleep problems may be directly related to autism, but others are not. Regardless, autism symptoms may make sleep problems worse.”
Few evidence-based treatments are available
Dr. Williams Buckley and colleagues developed the current guideline to evaluate which pharmacologic, behavioral, and complementary and alternative medicine (CAM) interventions improve bedtime resistance, sleep onset latency, sleep continuity, total sleep time, and daytime behavior in children and adolescents with ASD. The panel evaluated 900 abstracts of articles that had been included in systematic reviews, as well as 1,087 additional abstracts. One hundred thirty-nine articles were potentially relevant, 12 met criteria for data extraction, and eight were rated class III or higher and were included in the panel’s review.
The authors observed what they called a dearth of evidence-based treatments for sleep dysregulation in ASD. Evidence indicates that melatonin, with or without cognitive–behavioral therapy (CBT), improves several sleep outcomes, compared with placebo. “Evidence for other interventions is largely lacking,” wrote Dr. Williams Buckley and colleagues. They observed a lack of long-term safety data for melatonin in children, which they considered concerning, because melatonin affects the hypothalamic–gonadal axis and can potentially influence pubertal development.
Screening for comorbid conditions and concomitant medications
The guideline recommends that clinicians assess children with ASD and sleep disturbances for coexisting conditions and concomitant medications that could be contributing to these sleep disturbances. They should ensure that children receive appropriate treatment for coexisting conditions and adjust or discontinue potentially problematic medications appropriately, according to the guideline.
Furthermore, clinicians should counsel parents or guardians about behavioral strategies as a first-line treatment for improving sleep function. These strategies could be administered alone or with pharmacologic or neutraceutical approaches as needed, according to the authors. Suggested behavioral approaches include unmodified extinction (i.e., imposing a bedtime and ignoring a child’s protests), graduated extinction (i.e., ignoring protests for a specified period before responding), positive routines (i.e., establishing pre-bedtime calming rituals), and bedtime fading (i.e., putting a child to bed close to the time he or she begins to fall asleep).
If a child’s contributing coexisting conditions and medications have been addressed and behavioral strategies have not been helpful, clinicians should offer melatonin, according to the guideline. Because over-the-counter formulations contain variable concentrations of melatonin, clinicians should write a prescription for it or recommend high-purity pharmaceutical grade melatonin. The initial dose should be 1-3 mg/day at 60-30 minutes before bedtime. The dose can be titrated to 10 mg/day. Clinicians also should counsel children and their parents about potential adverse events of melatonin and the lack of long-term safety data, according to the guideline.
In addition, clinicians should advise children and parents that no evidence supports the routine use of weighted blankets or specialized mattress technology for improving sleep. Parents who ask about weighted blankets should be told that the reviewed trial reported no serious adverse events with this intervention, and that blankets could be a reasonable nonpharmacologic approach for some patients, according to the guideline.
Optimal outcome measures are undefined
Dr. Williams Buckley and colleagues also suggested areas for future research. Investigators have not yet defined optimal outcome measures (e.g., questionnaires, polysomnography, and actigraphy) that balance tolerability and accuracy, they wrote. Clinically important differences for most measures also have yet to be determined. Researchers should investigate whether long-term adverse events are associated with chronic melatonin use and study patients with ASD and comorbid mood disorders, wrote the authors. “Research tying the underlying neurobiology in early-life sleep disruption to behavior might help clinicians and researchers understand which treatments might work for which people with ASD,” they concluded.
The AAN supported the development of the guideline. Dr. Williams Buckley had no conflicts of interest. Six authors had conflicts of interest that the AAN deemed not significant enough to prevent their participation in the development of the guideline.
SOURCE: Williams Buckley A et al. Neurology. 2020;94:393-405. doi: 10.1212/WNL0000000000009033.
FROM NEUROLOGY
Key clinical point: The AAN has published a guideline on the treatment of sleep problems in children with autism.
Major finding: The guideline recommends behavioral strategies as a first-line treatment.
Study details: A review of 1,987 peer-reviewed studies.
Disclosures: The AAN funded the development of the guideline. The first author had no conflicts of interest, and the other authors had no significant conflicts.
Source: Williams Buckley A et al. Neurology. 2020;94:393-405. doi: 10.1212/WNL0000000000009033.