Multiple Sclerosis Hub

BOSTON—Two-year data from the phase III ADVANCE clinical trial support the maintained benefits of pegylated interferon beta-1a (125 µg) beyond one year in patients with relapsing-remitting multiple sclerosis (MS), with significantly greater efficacy over several key end points seen in patients receiving the drug every two weeks, as opposed to a four-week dosing regimen. These extension trial results were reported by Peter A. Calabresi, MD, at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

“Overall, pegylated interferon beta-1a seems to be a well-tolerated and safe approach to treating patients with relapsing-remitting MS,” said Dr. Calabresi, who is the Director of the Division of Immunology, Director of the Multiple Sclerosis Center, and Professor of Neurology at Johns Hopkins University in Baltimore.

Year one results of the ADVANCE study were published in the July issue of Lancet Neurology. The three-arm study compared placebo with subcutaneous pegylated interferon beta-1a (125 mg) given either every two weeks or every four weeks. Compared with placebo, both treatment arms had significant reductions in annualized relapse rates, which was the primary end point. Significant reductions were also seen in secondary end points—risk of relapse, disability progression, and number of new or newly enlarging T2 lesions. Two-week dosing showed greater benefits over four-week dosing. The safety profile in year one was largely consistent with the known safety of interferon and the side effects of the interferons.

Sustained Benefit
The purpose of the extension study was to examine maintenance of efficacy. “We want the drug to continue to work over a lifetime, so we compared patients in year one to patients in year two who were consistently on pegylated interferon,” Dr. Calabresi said. The researchers also compared patients continuously on pegylated interferon with those who were switched from placebo to active treatment to determine if treatment delay had any significant changes, compared with continuous treatment. The investigators also compared the efficacy of two-week dosing with four-week dosing.

Patient retention in year two was excellent—between 88% and 94% per arm, according to Dr. Calabresi. Compared with the delayed treatment group (those switched from placebo to active treatment), the researchers found a 37% reduction in annualized relapse rates in the two-week dosing arm and a 17% reduction in the four-week dosing arm. “So we saw a significant reduction in the two-week group with a trend in the four-week dosing arm,” Dr. Calabresi said.

Over two years, there was a 39% reduction in time to first relapse in the two-week dosing arm and a 19% reduction in the four-week dosing arm, compared with delayed treatment. Regarding 12-week confirmed disability progression, a 33% reduction was observed in the two-week dosing arm and a 25% reduction was found in the four-week dosing arm, again compared with delayed treatment. With regard to 24-week confirmed disability, there was a 41% reduction in the two-week dosing arm and a 9% reduction in the four-week dosing group. Proportions of patients with relapses meeting 24-week confirmed disability progression were also significantly reduced in the two-week dosing arm, compared with the four-week dosing arms or delayed treatment.

Significant reductions occurred in the two-week dosing group, as compared with the four-week group in all three MRI outcome measures. The mean number of new or newly enlarging T2-weighted hyperintense lesions was 14.8 in the delayed treatment group, 12.5 in the four-week dosing group, and five in the two-week dosing group. The mean number of gadolinium-enhancing lesions was 0.5 in the delayed treatment group, 0.7 in the four-week dosing group, and 0.2 in the two-week dosing group. The mean number of T1 hypointense lesions was 5.6 in the delayed treatment group, 4.9 in the four-week dosing group, and 2.3 in the two-week dosing group.

The same patterns were seen when looking at no MS disease activity overall. The two-week dosing group had significant decreases in the percentage of patients with no disease activity, as compared with delayed treatment, with the four-week doing group somewhere in between.

Regarding maintenance of efficacy between years one and two, the delayed treatment group that was switched from placebo to active treatment showed a reduction in the primary and secondary outcome measures. The greatest reductions were again seen in the two-week dosing group.

The two-year data revealed no surprises or new concerns with regard to safety or tolerability. Side effects were most commonly injection-site reactions in 68% and flu-like symptoms in 53%, but these events led to discontinuation in only 6% of patients. Although nine deaths occurred during the two years, an independent safety monitoring committee concluded that none of the deaths was related to the study drug.

The Outlook at Two Years
“The results over the two years are that pegylated interferon beta-1a has a positive effect on relapse rate and disease progression beyond the one-year placebo-controlled study period,” Dr. Calabresi said. “Over the two years, we saw a benefit of being on continuous pegylated interferon beta-1a, compared to the delayed treatment group. There were continued significant differences in many of the outcome measures in the two-week dosing group, as compared to the four-week dosing group.”

—Glenn S. Williams

BOSTON—Two-year data from the phase III ADVANCE clinical trial support the maintained benefits of pegylated interferon beta-1a (125 µg) beyond one year in patients with relapsing-remitting multiple sclerosis (MS), with significantly greater efficacy over several key end points seen in patients receiving the drug every two weeks, as opposed to a four-week dosing regimen. These extension trial results were reported by Peter A. Calabresi, MD, at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

“Overall, pegylated interferon beta-1a seems to be a well-tolerated and safe approach to treating patients with relapsing-remitting MS,” said Dr. Calabresi, who is the Director of the Division of Immunology, Director of the Multiple Sclerosis Center, and Professor of Neurology at Johns Hopkins University in Baltimore.

Year one results of the ADVANCE study were published in the July issue of Lancet Neurology. The three-arm study compared placebo with subcutaneous pegylated interferon beta-1a (125 mg) given either every two weeks or every four weeks. Compared with placebo, both treatment arms had significant reductions in annualized relapse rates, which was the primary end point. Significant reductions were also seen in secondary end points—risk of relapse, disability progression, and number of new or newly enlarging T2 lesions. Two-week dosing showed greater benefits over four-week dosing. The safety profile in year one was largely consistent with the known safety of interferon and the side effects of the interferons.

Sustained Benefit
The purpose of the extension study was to examine maintenance of efficacy. “We want the drug to continue to work over a lifetime, so we compared patients in year one to patients in year two who were consistently on pegylated interferon,” Dr. Calabresi said. The researchers also compared patients continuously on pegylated interferon with those who were switched from placebo to active treatment to determine if treatment delay had any significant changes, compared with continuous treatment. The investigators also compared the efficacy of two-week dosing with four-week dosing.

Patient retention in year two was excellent—between 88% and 94% per arm, according to Dr. Calabresi. Compared with the delayed treatment group (those switched from placebo to active treatment), the researchers found a 37% reduction in annualized relapse rates in the two-week dosing arm and a 17% reduction in the four-week dosing arm. “So we saw a significant reduction in the two-week group with a trend in the four-week dosing arm,” Dr. Calabresi said.

Over two years, there was a 39% reduction in time to first relapse in the two-week dosing arm and a 19% reduction in the four-week dosing arm, compared with delayed treatment. Regarding 12-week confirmed disability progression, a 33% reduction was observed in the two-week dosing arm and a 25% reduction was found in the four-week dosing arm, again compared with delayed treatment. With regard to 24-week confirmed disability, there was a 41% reduction in the two-week dosing arm and a 9% reduction in the four-week dosing group. Proportions of patients with relapses meeting 24-week confirmed disability progression were also significantly reduced in the two-week dosing arm, compared with the four-week dosing arms or delayed treatment.

Significant reductions occurred in the two-week dosing group, as compared with the four-week group in all three MRI outcome measures. The mean number of new or newly enlarging T2-weighted hyperintense lesions was 14.8 in the delayed treatment group, 12.5 in the four-week dosing group, and five in the two-week dosing group. The mean number of gadolinium-enhancing lesions was 0.5 in the delayed treatment group, 0.7 in the four-week dosing group, and 0.2 in the two-week dosing group. The mean number of T1 hypointense lesions was 5.6 in the delayed treatment group, 4.9 in the four-week dosing group, and 2.3 in the two-week dosing group.

The same patterns were seen when looking at no MS disease activity overall. The two-week dosing group had significant decreases in the percentage of patients with no disease activity, as compared with delayed treatment, with the four-week doing group somewhere in between.

Regarding maintenance of efficacy between years one and two, the delayed treatment group that was switched from placebo to active treatment showed a reduction in the primary and secondary outcome measures. The greatest reductions were again seen in the two-week dosing group.

The two-year data revealed no surprises or new concerns with regard to safety or tolerability. Side effects were most commonly injection-site reactions in 68% and flu-like symptoms in 53%, but these events led to discontinuation in only 6% of patients. Although nine deaths occurred during the two years, an independent safety monitoring committee concluded that none of the deaths was related to the study drug.

The Outlook at Two Years
“The results over the two years are that pegylated interferon beta-1a has a positive effect on relapse rate and disease progression beyond the one-year placebo-controlled study period,” Dr. Calabresi said. “Over the two years, we saw a benefit of being on continuous pegylated interferon beta-1a, compared to the delayed treatment group. There were continued significant differences in many of the outcome measures in the two-week dosing group, as compared to the four-week dosing group.”

—Glenn S. Williams

BOSTON—Two-year data from the phase III ADVANCE clinical trial support the maintained benefits of pegylated interferon beta-1a (125 µg) beyond one year in patients with relapsing-remitting multiple sclerosis (MS), with significantly greater efficacy over several key end points seen in patients receiving the drug every two weeks, as opposed to a four-week dosing regimen. These extension trial results were reported by Peter A. Calabresi, MD, at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

“Overall, pegylated interferon beta-1a seems to be a well-tolerated and safe approach to treating patients with relapsing-remitting MS,” said Dr. Calabresi, who is the Director of the Division of Immunology, Director of the Multiple Sclerosis Center, and Professor of Neurology at Johns Hopkins University in Baltimore.

Year one results of the ADVANCE study were published in the July issue of Lancet Neurology. The three-arm study compared placebo with subcutaneous pegylated interferon beta-1a (125 mg) given either every two weeks or every four weeks. Compared with placebo, both treatment arms had significant reductions in annualized relapse rates, which was the primary end point. Significant reductions were also seen in secondary end points—risk of relapse, disability progression, and number of new or newly enlarging T2 lesions. Two-week dosing showed greater benefits over four-week dosing. The safety profile in year one was largely consistent with the known safety of interferon and the side effects of the interferons.

Sustained Benefit
The purpose of the extension study was to examine maintenance of efficacy. “We want the drug to continue to work over a lifetime, so we compared patients in year one to patients in year two who were consistently on pegylated interferon,” Dr. Calabresi said. The researchers also compared patients continuously on pegylated interferon with those who were switched from placebo to active treatment to determine if treatment delay had any significant changes, compared with continuous treatment. The investigators also compared the efficacy of two-week dosing with four-week dosing.

Patient retention in year two was excellent—between 88% and 94% per arm, according to Dr. Calabresi. Compared with the delayed treatment group (those switched from placebo to active treatment), the researchers found a 37% reduction in annualized relapse rates in the two-week dosing arm and a 17% reduction in the four-week dosing arm. “So we saw a significant reduction in the two-week group with a trend in the four-week dosing arm,” Dr. Calabresi said.

Over two years, there was a 39% reduction in time to first relapse in the two-week dosing arm and a 19% reduction in the four-week dosing arm, compared with delayed treatment. Regarding 12-week confirmed disability progression, a 33% reduction was observed in the two-week dosing arm and a 25% reduction was found in the four-week dosing arm, again compared with delayed treatment. With regard to 24-week confirmed disability, there was a 41% reduction in the two-week dosing arm and a 9% reduction in the four-week dosing group. Proportions of patients with relapses meeting 24-week confirmed disability progression were also significantly reduced in the two-week dosing arm, compared with the four-week dosing arms or delayed treatment.

Significant reductions occurred in the two-week dosing group, as compared with the four-week group in all three MRI outcome measures. The mean number of new or newly enlarging T2-weighted hyperintense lesions was 14.8 in the delayed treatment group, 12.5 in the four-week dosing group, and five in the two-week dosing group. The mean number of gadolinium-enhancing lesions was 0.5 in the delayed treatment group, 0.7 in the four-week dosing group, and 0.2 in the two-week dosing group. The mean number of T1 hypointense lesions was 5.6 in the delayed treatment group, 4.9 in the four-week dosing group, and 2.3 in the two-week dosing group.

The same patterns were seen when looking at no MS disease activity overall. The two-week dosing group had significant decreases in the percentage of patients with no disease activity, as compared with delayed treatment, with the four-week doing group somewhere in between.

Regarding maintenance of efficacy between years one and two, the delayed treatment group that was switched from placebo to active treatment showed a reduction in the primary and secondary outcome measures. The greatest reductions were again seen in the two-week dosing group.

The two-year data revealed no surprises or new concerns with regard to safety or tolerability. Side effects were most commonly injection-site reactions in 68% and flu-like symptoms in 53%, but these events led to discontinuation in only 6% of patients. Although nine deaths occurred during the two years, an independent safety monitoring committee concluded that none of the deaths was related to the study drug.

The Outlook at Two Years
“The results over the two years are that pegylated interferon beta-1a has a positive effect on relapse rate and disease progression beyond the one-year placebo-controlled study period,” Dr. Calabresi said. “Over the two years, we saw a benefit of being on continuous pegylated interferon beta-1a, compared to the delayed treatment group. There were continued significant differences in many of the outcome measures in the two-week dosing group, as compared to the four-week dosing group.”

—Glenn S. Williams

BOSTON—Patients with multiple sclerosis (MS) have an increased risk of schizophrenia and bipolar disorder, researchers reported. In addition, the results of a retrospective analysis suggest that these disorders have shared etiologies.

“To our knowledge, this is the first large-scale study to test this association,” said Sreeram Ramagopalan, PhD, a research fellow at Evidera in London. “Caregivers should appropriately diagnose and manage these conditions in patients with MS.”

Recent studies have found similar risk factors for patients with schizophrenia, bipolar disorder, and MS, including immunogenetic associations, vitamin D deficiency, and infections. Dr. Ramagopalan and colleagues sought to test whether MS patients are at an increased risk of schizophrenia and bipolar disorder using the Hospital Episode Statistics database of hospital admissions in England.

The investigators analyzed a database of linked statistical records of hospital admissions and death certificates for all of England. The analysis included the years from 1999 to 2011 and examined data for 52 million people. The researchers determined rate ratios for psychiatric disease, comparing rates of schizophrenia and bipolar disorder in a cohort of all people in England admitted with MS (n = 82,176) with rates in a comparison cohort of patients admitted for various other, mainly minor, medical and surgical conditions (n = 9,818,240). Rates were based on person-days and were standardized by age (in five-year age groups), sex, calendar year of first recorded admission, region of residence, and quintile of patients’ Index of Multiple Deprivation score (as a measure of socioeconomic status), using the indirect method of standardization.

Patients with MS had significantly elevated risks for schizophrenia (rate ratio [RR] = 1.42); schizophrenia, schizotypal, and delusional disorders (RR = 2.08); and bipolar disorder (RR = 1.73). The researchers found these associations in males and females. The associations also were evident when the investigators identified a first schizophrenia or bipolar diagnosis at least a year after the first MS admission. The latter result suggests that the association is not a reflection of surveillance bias.

—Erik Greb

Does Overactive Bladder Correlate With MS Relapses or Progression?
Overactive bladder (OAB) with leakage is associated with a higher number of relapses and increased disease progression among patients with multiple sclerosis (MS), according to researchers.

Patients with OAB and leakage “should be closely monitored for indications of overall worsening function,” said Stacey S. Cofield, PhD, Associate Professor of Biostatistics at the University of Alabama at Birmingham, and colleagues.

Dr. Cofield and colleagues investigated the relationship between self-reported bladder dysfunction and relapses and severity of disability during five years of follow-up. The researchers examined data from the North American Research Committee on MS (NARCOMS) database, a voluntary registry for people with MS that involves an enrollment survey and semiannual updates. They included participants who responded to questions about bladder function in fall 2005. Eligible participants were US residents with no surgical alterations to the bladder who completed one or more update survey annually from 2005 through 2010.

The investigators classified respondents in 2005 as having wet OAB (ie, urgency with urgency-related leakage), dry OAB (ie, urgency without urgency-related leakage), or no OAB. They defined progression as a one-point increase in Patient-Determined Disease Steps (PDDS) from 2005 to 2010 and at 2010.

A total of 4,870 respondents were included in the analysis. Approximately 74% of respondents were female. About 94% of participants were Caucasian, and the population’s mean age was approximately 51. Respondents’ mean disease duration in 2005 was 12 years.

Of all respondents, 60.2% were classified as having wet OAB, 15.2% were classified as having dry OAB, and 24.6% were classified as having no OAB. Among participants with wet OAB, 50.8% reported slight incontinence, 30.6% reported moderate incontinence, and 18.7% reported great incontinence. In 2005, patients with wet OAB were older and had a longer disease duration than the other respondents.

The proportion of respondents reporting any relapse from 2005 to 2010 did not differ across groups, but patients with wet OAB were more likely to report more than three relapses and PDDS progression. From 2005 to 2010, 55% of patients with wet OAB reported three or more relapses, compared with 51% of patients with dry OAB and 52% of patients with no OAB. In the same period, 37% of respondents with wet OAB reported progression, compared with 33% of respondents with dry OAB and 28% of respondents with no OAB. In addition, older age and longer disease duration were associated significantly with PDDS progression.

A higher proportion of patients with wet OAB in 2005 reported being severely bothered by urinary or bladder, bowel, and sexual dysfunction in 2010. Approximately 21% of respondents with wet OAB were severely bothered by urinary or bladder dysfunction in 2010, compared with 6% of patients with dry OAB and 5% of patients with no OAB. Eleven percent of patients with wet OAB were severely bothered by bowel dysfunction in 2010, compared with 5% of patients with dry OAB and 5% of patients with no OAB. In addition, 25% of participants with wet OAB were severely bothered by sexual dysfunction in 2010, compared with 5% of participants with dry OAB and 13% of participants with no OAB.

—Erik Greb

BOSTON—Patients with multiple sclerosis (MS) have an increased risk of schizophrenia and bipolar disorder, researchers reported. In addition, the results of a retrospective analysis suggest that these disorders have shared etiologies.

“To our knowledge, this is the first large-scale study to test this association,” said Sreeram Ramagopalan, PhD, a research fellow at Evidera in London. “Caregivers should appropriately diagnose and manage these conditions in patients with MS.”

Recent studies have found similar risk factors for patients with schizophrenia, bipolar disorder, and MS, including immunogenetic associations, vitamin D deficiency, and infections. Dr. Ramagopalan and colleagues sought to test whether MS patients are at an increased risk of schizophrenia and bipolar disorder using the Hospital Episode Statistics database of hospital admissions in England.

The investigators analyzed a database of linked statistical records of hospital admissions and death certificates for all of England. The analysis included the years from 1999 to 2011 and examined data for 52 million people. The researchers determined rate ratios for psychiatric disease, comparing rates of schizophrenia and bipolar disorder in a cohort of all people in England admitted with MS (n = 82,176) with rates in a comparison cohort of patients admitted for various other, mainly minor, medical and surgical conditions (n = 9,818,240). Rates were based on person-days and were standardized by age (in five-year age groups), sex, calendar year of first recorded admission, region of residence, and quintile of patients’ Index of Multiple Deprivation score (as a measure of socioeconomic status), using the indirect method of standardization.

Patients with MS had significantly elevated risks for schizophrenia (rate ratio [RR] = 1.42); schizophrenia, schizotypal, and delusional disorders (RR = 2.08); and bipolar disorder (RR = 1.73). The researchers found these associations in males and females. The associations also were evident when the investigators identified a first schizophrenia or bipolar diagnosis at least a year after the first MS admission. The latter result suggests that the association is not a reflection of surveillance bias.

—Erik Greb

Does Overactive Bladder Correlate With MS Relapses or Progression?
Overactive bladder (OAB) with leakage is associated with a higher number of relapses and increased disease progression among patients with multiple sclerosis (MS), according to researchers.

Patients with OAB and leakage “should be closely monitored for indications of overall worsening function,” said Stacey S. Cofield, PhD, Associate Professor of Biostatistics at the University of Alabama at Birmingham, and colleagues.

Dr. Cofield and colleagues investigated the relationship between self-reported bladder dysfunction and relapses and severity of disability during five years of follow-up. The researchers examined data from the North American Research Committee on MS (NARCOMS) database, a voluntary registry for people with MS that involves an enrollment survey and semiannual updates. They included participants who responded to questions about bladder function in fall 2005. Eligible participants were US residents with no surgical alterations to the bladder who completed one or more update survey annually from 2005 through 2010.

The investigators classified respondents in 2005 as having wet OAB (ie, urgency with urgency-related leakage), dry OAB (ie, urgency without urgency-related leakage), or no OAB. They defined progression as a one-point increase in Patient-Determined Disease Steps (PDDS) from 2005 to 2010 and at 2010.

A total of 4,870 respondents were included in the analysis. Approximately 74% of respondents were female. About 94% of participants were Caucasian, and the population’s mean age was approximately 51. Respondents’ mean disease duration in 2005 was 12 years.

Of all respondents, 60.2% were classified as having wet OAB, 15.2% were classified as having dry OAB, and 24.6% were classified as having no OAB. Among participants with wet OAB, 50.8% reported slight incontinence, 30.6% reported moderate incontinence, and 18.7% reported great incontinence. In 2005, patients with wet OAB were older and had a longer disease duration than the other respondents.

The proportion of respondents reporting any relapse from 2005 to 2010 did not differ across groups, but patients with wet OAB were more likely to report more than three relapses and PDDS progression. From 2005 to 2010, 55% of patients with wet OAB reported three or more relapses, compared with 51% of patients with dry OAB and 52% of patients with no OAB. In the same period, 37% of respondents with wet OAB reported progression, compared with 33% of respondents with dry OAB and 28% of respondents with no OAB. In addition, older age and longer disease duration were associated significantly with PDDS progression.

A higher proportion of patients with wet OAB in 2005 reported being severely bothered by urinary or bladder, bowel, and sexual dysfunction in 2010. Approximately 21% of respondents with wet OAB were severely bothered by urinary or bladder dysfunction in 2010, compared with 6% of patients with dry OAB and 5% of patients with no OAB. Eleven percent of patients with wet OAB were severely bothered by bowel dysfunction in 2010, compared with 5% of patients with dry OAB and 5% of patients with no OAB. In addition, 25% of participants with wet OAB were severely bothered by sexual dysfunction in 2010, compared with 5% of participants with dry OAB and 13% of participants with no OAB.

—Erik Greb

BOSTON—Patients with multiple sclerosis (MS) have an increased risk of schizophrenia and bipolar disorder, researchers reported. In addition, the results of a retrospective analysis suggest that these disorders have shared etiologies.

“To our knowledge, this is the first large-scale study to test this association,” said Sreeram Ramagopalan, PhD, a research fellow at Evidera in London. “Caregivers should appropriately diagnose and manage these conditions in patients with MS.”

Recent studies have found similar risk factors for patients with schizophrenia, bipolar disorder, and MS, including immunogenetic associations, vitamin D deficiency, and infections. Dr. Ramagopalan and colleagues sought to test whether MS patients are at an increased risk of schizophrenia and bipolar disorder using the Hospital Episode Statistics database of hospital admissions in England.

The investigators analyzed a database of linked statistical records of hospital admissions and death certificates for all of England. The analysis included the years from 1999 to 2011 and examined data for 52 million people. The researchers determined rate ratios for psychiatric disease, comparing rates of schizophrenia and bipolar disorder in a cohort of all people in England admitted with MS (n = 82,176) with rates in a comparison cohort of patients admitted for various other, mainly minor, medical and surgical conditions (n = 9,818,240). Rates were based on person-days and were standardized by age (in five-year age groups), sex, calendar year of first recorded admission, region of residence, and quintile of patients’ Index of Multiple Deprivation score (as a measure of socioeconomic status), using the indirect method of standardization.

Patients with MS had significantly elevated risks for schizophrenia (rate ratio [RR] = 1.42); schizophrenia, schizotypal, and delusional disorders (RR = 2.08); and bipolar disorder (RR = 1.73). The researchers found these associations in males and females. The associations also were evident when the investigators identified a first schizophrenia or bipolar diagnosis at least a year after the first MS admission. The latter result suggests that the association is not a reflection of surveillance bias.

—Erik Greb

Does Overactive Bladder Correlate With MS Relapses or Progression?
Overactive bladder (OAB) with leakage is associated with a higher number of relapses and increased disease progression among patients with multiple sclerosis (MS), according to researchers.

Patients with OAB and leakage “should be closely monitored for indications of overall worsening function,” said Stacey S. Cofield, PhD, Associate Professor of Biostatistics at the University of Alabama at Birmingham, and colleagues.

Dr. Cofield and colleagues investigated the relationship between self-reported bladder dysfunction and relapses and severity of disability during five years of follow-up. The researchers examined data from the North American Research Committee on MS (NARCOMS) database, a voluntary registry for people with MS that involves an enrollment survey and semiannual updates. They included participants who responded to questions about bladder function in fall 2005. Eligible participants were US residents with no surgical alterations to the bladder who completed one or more update survey annually from 2005 through 2010.

The investigators classified respondents in 2005 as having wet OAB (ie, urgency with urgency-related leakage), dry OAB (ie, urgency without urgency-related leakage), or no OAB. They defined progression as a one-point increase in Patient-Determined Disease Steps (PDDS) from 2005 to 2010 and at 2010.

A total of 4,870 respondents were included in the analysis. Approximately 74% of respondents were female. About 94% of participants were Caucasian, and the population’s mean age was approximately 51. Respondents’ mean disease duration in 2005 was 12 years.

Of all respondents, 60.2% were classified as having wet OAB, 15.2% were classified as having dry OAB, and 24.6% were classified as having no OAB. Among participants with wet OAB, 50.8% reported slight incontinence, 30.6% reported moderate incontinence, and 18.7% reported great incontinence. In 2005, patients with wet OAB were older and had a longer disease duration than the other respondents.

The proportion of respondents reporting any relapse from 2005 to 2010 did not differ across groups, but patients with wet OAB were more likely to report more than three relapses and PDDS progression. From 2005 to 2010, 55% of patients with wet OAB reported three or more relapses, compared with 51% of patients with dry OAB and 52% of patients with no OAB. In the same period, 37% of respondents with wet OAB reported progression, compared with 33% of respondents with dry OAB and 28% of respondents with no OAB. In addition, older age and longer disease duration were associated significantly with PDDS progression.

A higher proportion of patients with wet OAB in 2005 reported being severely bothered by urinary or bladder, bowel, and sexual dysfunction in 2010. Approximately 21% of respondents with wet OAB were severely bothered by urinary or bladder dysfunction in 2010, compared with 6% of patients with dry OAB and 5% of patients with no OAB. Eleven percent of patients with wet OAB were severely bothered by bowel dysfunction in 2010, compared with 5% of patients with dry OAB and 5% of patients with no OAB. In addition, 25% of participants with wet OAB were severely bothered by sexual dysfunction in 2010, compared with 5% of participants with dry OAB and 13% of participants with no OAB.

—Erik Greb

BOSTON—Diet does not appear to contribute to the development of multiple sclerosis (MS), according to findings presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

None of three dietary indices measured at baseline—the Alternative Healthy Eating Index-2010 (AHEI-2010), the Alternate Mediterranean Diet Index (aMED), and the Dietary Approaches to Stop Hypertension Index (DASH)—was significantly associated with the risk of developing MS in two longitudinal cohort studies, Dalia Rotstein, MD, Clinical Fellow in Neurology, Brigham and Women’s Hospital, Cambridge, Massachusetts, reported. Dr. Rotstein’s group prospectively followed more than 185,000 women from the Nurses’ Health Study (NHS) and the NHS II.

After adjustment for known confounders of MS risk—including age, latitude of residence at age 15, BMI at age 18, pack-years of smoking, total energy intake, supplemental vitamin D intake, and ethnicity—the investigators found that the pooled relative risk of MS for the highest versus the lowest quintile of scores for each index was 0.89 for the AHEI-2010, 1.10 for aMED, and 1.30 for DASH.

A principal-components analysis identified two general dietary patterns among the subjects. One was a “Western” dietary pattern with high intake of red and processed meats, refined grains, and sweets, and the other was a “prudent” dietary pattern with high intake of vegetables, fruit, legumes, fish, poultry, and whole grains. Neither was associated with MS risk (relative risk for the highest vs lowest quintile of scores, 0.71 and 1.09, respectively). The results were similar when looking at mean cumulative dietary scores and when looking at the two cohorts separately.

An exception in the analysis using mean cumulative dietary score was for the Western dietary pattern, which was shown to have a significant inverse association with MS risk (relative risk, 0.66). “This just met statistical significance, and we believe that this result is an artifact,” Dr. Rotstein said.

Study participants completed semiquantitative food frequency questionnaires every four years, beginning in 1984 for the NHS and in 1991 for NHS II. The MS cases were documented as of 2004 for NHS (130 cases) and as of 2009 for NHS II (350 cases).

With the exception of studies on vitamin D intake, prior studies have yielded null or inconsistent results with respect to the role of diet in MS development, and most have been limited by a focus on individual dietary elements and by small sample size.

The current study is the first large, prospective, population-based study to investigate the relationship, and it shows no evidence of an association between overall dietary quality and MS, Dr. Rotstein said.

The study is limited by the inherent subjectivity in dietary scores and by a basis in population norms rather than ideal consumption patterns. Also, the study is conceived around recommendations for cardiovascular health, but other dietary patterns may be more relevant for immunologic health, she said, noting that additional study is needed to determine if dietary quality and individual dietary elements in the early years play a role in MS development.

—Sharon Worcester

BOSTON—Diet does not appear to contribute to the development of multiple sclerosis (MS), according to findings presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

None of three dietary indices measured at baseline—the Alternative Healthy Eating Index-2010 (AHEI-2010), the Alternate Mediterranean Diet Index (aMED), and the Dietary Approaches to Stop Hypertension Index (DASH)—was significantly associated with the risk of developing MS in two longitudinal cohort studies, Dalia Rotstein, MD, Clinical Fellow in Neurology, Brigham and Women’s Hospital, Cambridge, Massachusetts, reported. Dr. Rotstein’s group prospectively followed more than 185,000 women from the Nurses’ Health Study (NHS) and the NHS II.

After adjustment for known confounders of MS risk—including age, latitude of residence at age 15, BMI at age 18, pack-years of smoking, total energy intake, supplemental vitamin D intake, and ethnicity—the investigators found that the pooled relative risk of MS for the highest versus the lowest quintile of scores for each index was 0.89 for the AHEI-2010, 1.10 for aMED, and 1.30 for DASH.

A principal-components analysis identified two general dietary patterns among the subjects. One was a “Western” dietary pattern with high intake of red and processed meats, refined grains, and sweets, and the other was a “prudent” dietary pattern with high intake of vegetables, fruit, legumes, fish, poultry, and whole grains. Neither was associated with MS risk (relative risk for the highest vs lowest quintile of scores, 0.71 and 1.09, respectively). The results were similar when looking at mean cumulative dietary scores and when looking at the two cohorts separately.

An exception in the analysis using mean cumulative dietary score was for the Western dietary pattern, which was shown to have a significant inverse association with MS risk (relative risk, 0.66). “This just met statistical significance, and we believe that this result is an artifact,” Dr. Rotstein said.

Study participants completed semiquantitative food frequency questionnaires every four years, beginning in 1984 for the NHS and in 1991 for NHS II. The MS cases were documented as of 2004 for NHS (130 cases) and as of 2009 for NHS II (350 cases).

With the exception of studies on vitamin D intake, prior studies have yielded null or inconsistent results with respect to the role of diet in MS development, and most have been limited by a focus on individual dietary elements and by small sample size.

The current study is the first large, prospective, population-based study to investigate the relationship, and it shows no evidence of an association between overall dietary quality and MS, Dr. Rotstein said.

The study is limited by the inherent subjectivity in dietary scores and by a basis in population norms rather than ideal consumption patterns. Also, the study is conceived around recommendations for cardiovascular health, but other dietary patterns may be more relevant for immunologic health, she said, noting that additional study is needed to determine if dietary quality and individual dietary elements in the early years play a role in MS development.

—Sharon Worcester

BOSTON—Diet does not appear to contribute to the development of multiple sclerosis (MS), according to findings presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

None of three dietary indices measured at baseline—the Alternative Healthy Eating Index-2010 (AHEI-2010), the Alternate Mediterranean Diet Index (aMED), and the Dietary Approaches to Stop Hypertension Index (DASH)—was significantly associated with the risk of developing MS in two longitudinal cohort studies, Dalia Rotstein, MD, Clinical Fellow in Neurology, Brigham and Women’s Hospital, Cambridge, Massachusetts, reported. Dr. Rotstein’s group prospectively followed more than 185,000 women from the Nurses’ Health Study (NHS) and the NHS II.

After adjustment for known confounders of MS risk—including age, latitude of residence at age 15, BMI at age 18, pack-years of smoking, total energy intake, supplemental vitamin D intake, and ethnicity—the investigators found that the pooled relative risk of MS for the highest versus the lowest quintile of scores for each index was 0.89 for the AHEI-2010, 1.10 for aMED, and 1.30 for DASH.

A principal-components analysis identified two general dietary patterns among the subjects. One was a “Western” dietary pattern with high intake of red and processed meats, refined grains, and sweets, and the other was a “prudent” dietary pattern with high intake of vegetables, fruit, legumes, fish, poultry, and whole grains. Neither was associated with MS risk (relative risk for the highest vs lowest quintile of scores, 0.71 and 1.09, respectively). The results were similar when looking at mean cumulative dietary scores and when looking at the two cohorts separately.

An exception in the analysis using mean cumulative dietary score was for the Western dietary pattern, which was shown to have a significant inverse association with MS risk (relative risk, 0.66). “This just met statistical significance, and we believe that this result is an artifact,” Dr. Rotstein said.

Study participants completed semiquantitative food frequency questionnaires every four years, beginning in 1984 for the NHS and in 1991 for NHS II. The MS cases were documented as of 2004 for NHS (130 cases) and as of 2009 for NHS II (350 cases).

With the exception of studies on vitamin D intake, prior studies have yielded null or inconsistent results with respect to the role of diet in MS development, and most have been limited by a focus on individual dietary elements and by small sample size.

The current study is the first large, prospective, population-based study to investigate the relationship, and it shows no evidence of an association between overall dietary quality and MS, Dr. Rotstein said.

The study is limited by the inherent subjectivity in dietary scores and by a basis in population norms rather than ideal consumption patterns. Also, the study is conceived around recommendations for cardiovascular health, but other dietary patterns may be more relevant for immunologic health, she said, noting that additional study is needed to determine if dietary quality and individual dietary elements in the early years play a role in MS development.

—Sharon Worcester

BOSTON—Long-term treatment with interferon beta-1a or glatiramer acetate has the potential to be cost effective and to alter the natural history of relapsing-remitting multiple sclerosis (MS), according to findings from a six-year observational study presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

In 4,137 patients with relapsing-remitting MS who were followed for a median of six years, the observed increase in the Expanded Disability Status Scale (EDSS) scores was lower among treated patients than the increase seen in a natural history cohort that served as a comparator group (relative rates, 0.76 using a continuous Markov model and 0.61 using a multilevel model).

Results of Treatment Exceeded Predictions
The observed progression for utility—a quality of life measure derived from the EDSS scores, and the primary outcome of the study—was consistent with this finding (relative rates of 0.58 and 0.56, according to the two models, respectively), said Jacqueline Palace, BM, Consultant Neurologist at the University of Oxford, United Kingdom.

The researchers had predicted that treatment would reduce the observed progression for utility by 38%, compared with the natural history cohort. Data, however, indicated a reduction of about 42%, which was better than predicted, added Dr. Palace. A range of sensitivity analyses that examined the potential for various biases consistently demonstrated better outcomes in the treated patients, compared with the natural history cohort. If sustained over 20 years, the magnitude of the treatment effect observed in this study would be consistent with a predefined cost-effectiveness target of approximately $58,400 per quality-adjusted life-year, said Dr. Palace.

Patients included in this study were adults with a mean age of 38 and a mean age at disease onset of 31. Most participants (76%) were women. Mean disease duration was 7.7 years at baseline, and the patients had a mean of three relapses over the previous two years. Mean baseline EDSS score was 3.06.

The UK’s Risk-Sharing Scheme
“In 2002, the National Institute of Clinical Excellence [NICE], which is the UK body that sets the guidelines that decide [which drugs] should be available under the National Health Service [NHS], concluded that beta-interferon and glatiramer acetate were not cost-effective during the short-term, and thus it recommended that [they] couldn’t be available under the NHS at that stage,” explained Dr. Palace.

The NICE did state, however, that if the drugs’ effects were maintained over the long term, the drugs might be cost effective. The institute invited the Department of Health to “try and find a way to make the drugs available in a cost-effective manner,” said Dr. Palace. “This was the birth of the Risk-Sharing Scheme, and it is a way of providing disease-modifying therapies to patients cost effectively.”

At the start of the scheme, the drug prices were reduced according to a NICE model of cost efficacy. Prices were set at the equivalent of $58,400/quality-adjusted life-year. A price adjustment would have been required to achieve cost effectiveness if the outcomes of the treated patients had been worse than predicted. “We were allowed to reach this target over a 20-year lifespan, and the idea was to monitor a clinical cohort of patients, measuring their EDSS scores,” said Dr. Palace. The natural history dataset was used as a virtual placebo.

The investigation was the largest observational study to measure the effect and cost-effectiveness of interferon beta-1a and glatiramer acetate. The findings provide evidence that the treatment alters the natural history of relapsing-remitting MS, Dr. Palace concluded.

—Sharon Worcester

BOSTON—Long-term treatment with interferon beta-1a or glatiramer acetate has the potential to be cost effective and to alter the natural history of relapsing-remitting multiple sclerosis (MS), according to findings from a six-year observational study presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

In 4,137 patients with relapsing-remitting MS who were followed for a median of six years, the observed increase in the Expanded Disability Status Scale (EDSS) scores was lower among treated patients than the increase seen in a natural history cohort that served as a comparator group (relative rates, 0.76 using a continuous Markov model and 0.61 using a multilevel model).

Results of Treatment Exceeded Predictions
The observed progression for utility—a quality of life measure derived from the EDSS scores, and the primary outcome of the study—was consistent with this finding (relative rates of 0.58 and 0.56, according to the two models, respectively), said Jacqueline Palace, BM, Consultant Neurologist at the University of Oxford, United Kingdom.

The researchers had predicted that treatment would reduce the observed progression for utility by 38%, compared with the natural history cohort. Data, however, indicated a reduction of about 42%, which was better than predicted, added Dr. Palace. A range of sensitivity analyses that examined the potential for various biases consistently demonstrated better outcomes in the treated patients, compared with the natural history cohort. If sustained over 20 years, the magnitude of the treatment effect observed in this study would be consistent with a predefined cost-effectiveness target of approximately $58,400 per quality-adjusted life-year, said Dr. Palace.

Patients included in this study were adults with a mean age of 38 and a mean age at disease onset of 31. Most participants (76%) were women. Mean disease duration was 7.7 years at baseline, and the patients had a mean of three relapses over the previous two years. Mean baseline EDSS score was 3.06.

The UK’s Risk-Sharing Scheme
“In 2002, the National Institute of Clinical Excellence [NICE], which is the UK body that sets the guidelines that decide [which drugs] should be available under the National Health Service [NHS], concluded that beta-interferon and glatiramer acetate were not cost-effective during the short-term, and thus it recommended that [they] couldn’t be available under the NHS at that stage,” explained Dr. Palace.

The NICE did state, however, that if the drugs’ effects were maintained over the long term, the drugs might be cost effective. The institute invited the Department of Health to “try and find a way to make the drugs available in a cost-effective manner,” said Dr. Palace. “This was the birth of the Risk-Sharing Scheme, and it is a way of providing disease-modifying therapies to patients cost effectively.”

At the start of the scheme, the drug prices were reduced according to a NICE model of cost efficacy. Prices were set at the equivalent of $58,400/quality-adjusted life-year. A price adjustment would have been required to achieve cost effectiveness if the outcomes of the treated patients had been worse than predicted. “We were allowed to reach this target over a 20-year lifespan, and the idea was to monitor a clinical cohort of patients, measuring their EDSS scores,” said Dr. Palace. The natural history dataset was used as a virtual placebo.

The investigation was the largest observational study to measure the effect and cost-effectiveness of interferon beta-1a and glatiramer acetate. The findings provide evidence that the treatment alters the natural history of relapsing-remitting MS, Dr. Palace concluded.

—Sharon Worcester

BOSTON—Long-term treatment with interferon beta-1a or glatiramer acetate has the potential to be cost effective and to alter the natural history of relapsing-remitting multiple sclerosis (MS), according to findings from a six-year observational study presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

In 4,137 patients with relapsing-remitting MS who were followed for a median of six years, the observed increase in the Expanded Disability Status Scale (EDSS) scores was lower among treated patients than the increase seen in a natural history cohort that served as a comparator group (relative rates, 0.76 using a continuous Markov model and 0.61 using a multilevel model).

Results of Treatment Exceeded Predictions
The observed progression for utility—a quality of life measure derived from the EDSS scores, and the primary outcome of the study—was consistent with this finding (relative rates of 0.58 and 0.56, according to the two models, respectively), said Jacqueline Palace, BM, Consultant Neurologist at the University of Oxford, United Kingdom.

The researchers had predicted that treatment would reduce the observed progression for utility by 38%, compared with the natural history cohort. Data, however, indicated a reduction of about 42%, which was better than predicted, added Dr. Palace. A range of sensitivity analyses that examined the potential for various biases consistently demonstrated better outcomes in the treated patients, compared with the natural history cohort. If sustained over 20 years, the magnitude of the treatment effect observed in this study would be consistent with a predefined cost-effectiveness target of approximately $58,400 per quality-adjusted life-year, said Dr. Palace.

Patients included in this study were adults with a mean age of 38 and a mean age at disease onset of 31. Most participants (76%) were women. Mean disease duration was 7.7 years at baseline, and the patients had a mean of three relapses over the previous two years. Mean baseline EDSS score was 3.06.

The UK’s Risk-Sharing Scheme
“In 2002, the National Institute of Clinical Excellence [NICE], which is the UK body that sets the guidelines that decide [which drugs] should be available under the National Health Service [NHS], concluded that beta-interferon and glatiramer acetate were not cost-effective during the short-term, and thus it recommended that [they] couldn’t be available under the NHS at that stage,” explained Dr. Palace.

The NICE did state, however, that if the drugs’ effects were maintained over the long term, the drugs might be cost effective. The institute invited the Department of Health to “try and find a way to make the drugs available in a cost-effective manner,” said Dr. Palace. “This was the birth of the Risk-Sharing Scheme, and it is a way of providing disease-modifying therapies to patients cost effectively.”

At the start of the scheme, the drug prices were reduced according to a NICE model of cost efficacy. Prices were set at the equivalent of $58,400/quality-adjusted life-year. A price adjustment would have been required to achieve cost effectiveness if the outcomes of the treated patients had been worse than predicted. “We were allowed to reach this target over a 20-year lifespan, and the idea was to monitor a clinical cohort of patients, measuring their EDSS scores,” said Dr. Palace. The natural history dataset was used as a virtual placebo.

The investigation was the largest observational study to measure the effect and cost-effectiveness of interferon beta-1a and glatiramer acetate. The findings provide evidence that the treatment alters the natural history of relapsing-remitting MS, Dr. Palace concluded.

—Sharon Worcester

BOSTON—A novel compound called fluorosamine appears to promote remyelination and reduce inflammation in animal models of experimental autoimmune encephalomyelitis (EAE), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Results indicate that the molecule potentially could benefit patients with multiple sclerosis (MS).

V. Wee Yong, PhD, Professor and Head of Translational Neuroscience at the University of Calgary in Canada, and colleagues initiated EAE in animals and allowed them to develop signs of disability. The investigators began treating some of the animals with fluorosamine daily and some with vehicle daily. Disease severity was reduced among animals that received fluorosamine, compared with animals that received vehicle. “If we initiate treatment with fluorosamine at peak EAE, we find that while vehicle-treated animals continue to have significant disability, treatment with fluorosamine reduces clinical severity,” said Dr. Yong.

Investigating CSPGs
The current study follows the investigators’ previous examinations of chondroitin sulfate proteoglycans (CSPGs). This class of chemicals includes versican, aggrecan, neurocan, and brevican. In 2001, Sobel and colleagues found neurocan, veriscan, and aggrecan at the edge of an active MS lesion. In other conditions such as traumatic spinal cord injury, CSPGs have been identified as inhibitors of axonal regeneration.

To determine whether CSPGs affect remyelination, Dr. Yong and colleagues investigated a model of demyelination and remyelination in which lysolecithin was injected into an animal’s spinal cord dorsal column. Within three days of demyelination, the researchers found deposition of versican V1 around cells and in acellular areas in the extracellular matrix. In a later study, Dr. Yong and colleagues found that CSPGs were cleared during the process of remyelination that followed lysolecithin-induced demyelination. The group also found that reducing the deposition of CSPGs promoted remyelination.

In 2012, Dr. Yong’s group performed in vitro stripe assays of human oligodendrocyte precursor cells (OPCs). When the human OPCs were plated onto a setup in which stripes had been coated with bovine serum albumin, the OPCs flourished in environments with and without bovine serum albumin. In contrast, OPCs sent few processes into stripes coated with CSPGs. This finding emphasizes “the nonpermissive nature of the CSPGs,” said Dr. Yong.

The Development of Fluorosamine
To reduce the production of CSPGs following injury, Dr. Yong and colleagues designed fluorosamine. They found that peracetylating fluorosamine with many acetyl groups facilitated the compound’s entry into cells. In an in vitro proof-of-concept study, the investigators activated astrocytes with TGF-β to increase their production of CSPGs. When the astrocytes were incubated with peracetylated fluorosamine, the group observed a “robust downregulation of CSPG production by activated astrocytes,” said Dr. Yong.

In an in vivo proof-of-concept study, the researchers induced demyelination in animals by injecting their spinal cords with lysolecithin. After the animals received fluorosamine treatment, the investigators observed significantly reduced expression of versican in the injured spinal cords.

When the researchers stained tissue samples for oligodendrocytes using OLIG2 and GSTπ, they found a greater number of oligodendrocytes within lesions in animals that underwent lysolecithin-induced demyelination and subsequent treatment with fluorosamine than in animals with demyelination that were untreated. In addition, animals that were treated with fluorosamine had more myelinated profiles than untreated animals. A separate study indicated that fluorosamine reduced inflammation in tissue culture by inhibiting macrophage activation.

—Erik Greb

BOSTON—A novel compound called fluorosamine appears to promote remyelination and reduce inflammation in animal models of experimental autoimmune encephalomyelitis (EAE), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Results indicate that the molecule potentially could benefit patients with multiple sclerosis (MS).

V. Wee Yong, PhD, Professor and Head of Translational Neuroscience at the University of Calgary in Canada, and colleagues initiated EAE in animals and allowed them to develop signs of disability. The investigators began treating some of the animals with fluorosamine daily and some with vehicle daily. Disease severity was reduced among animals that received fluorosamine, compared with animals that received vehicle. “If we initiate treatment with fluorosamine at peak EAE, we find that while vehicle-treated animals continue to have significant disability, treatment with fluorosamine reduces clinical severity,” said Dr. Yong.

Investigating CSPGs
The current study follows the investigators’ previous examinations of chondroitin sulfate proteoglycans (CSPGs). This class of chemicals includes versican, aggrecan, neurocan, and brevican. In 2001, Sobel and colleagues found neurocan, veriscan, and aggrecan at the edge of an active MS lesion. In other conditions such as traumatic spinal cord injury, CSPGs have been identified as inhibitors of axonal regeneration.

To determine whether CSPGs affect remyelination, Dr. Yong and colleagues investigated a model of demyelination and remyelination in which lysolecithin was injected into an animal’s spinal cord dorsal column. Within three days of demyelination, the researchers found deposition of versican V1 around cells and in acellular areas in the extracellular matrix. In a later study, Dr. Yong and colleagues found that CSPGs were cleared during the process of remyelination that followed lysolecithin-induced demyelination. The group also found that reducing the deposition of CSPGs promoted remyelination.

In 2012, Dr. Yong’s group performed in vitro stripe assays of human oligodendrocyte precursor cells (OPCs). When the human OPCs were plated onto a setup in which stripes had been coated with bovine serum albumin, the OPCs flourished in environments with and without bovine serum albumin. In contrast, OPCs sent few processes into stripes coated with CSPGs. This finding emphasizes “the nonpermissive nature of the CSPGs,” said Dr. Yong.

The Development of Fluorosamine
To reduce the production of CSPGs following injury, Dr. Yong and colleagues designed fluorosamine. They found that peracetylating fluorosamine with many acetyl groups facilitated the compound’s entry into cells. In an in vitro proof-of-concept study, the investigators activated astrocytes with TGF-β to increase their production of CSPGs. When the astrocytes were incubated with peracetylated fluorosamine, the group observed a “robust downregulation of CSPG production by activated astrocytes,” said Dr. Yong.

In an in vivo proof-of-concept study, the researchers induced demyelination in animals by injecting their spinal cords with lysolecithin. After the animals received fluorosamine treatment, the investigators observed significantly reduced expression of versican in the injured spinal cords.

When the researchers stained tissue samples for oligodendrocytes using OLIG2 and GSTπ, they found a greater number of oligodendrocytes within lesions in animals that underwent lysolecithin-induced demyelination and subsequent treatment with fluorosamine than in animals with demyelination that were untreated. In addition, animals that were treated with fluorosamine had more myelinated profiles than untreated animals. A separate study indicated that fluorosamine reduced inflammation in tissue culture by inhibiting macrophage activation.

—Erik Greb

BOSTON—A novel compound called fluorosamine appears to promote remyelination and reduce inflammation in animal models of experimental autoimmune encephalomyelitis (EAE), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. Results indicate that the molecule potentially could benefit patients with multiple sclerosis (MS).

V. Wee Yong, PhD, Professor and Head of Translational Neuroscience at the University of Calgary in Canada, and colleagues initiated EAE in animals and allowed them to develop signs of disability. The investigators began treating some of the animals with fluorosamine daily and some with vehicle daily. Disease severity was reduced among animals that received fluorosamine, compared with animals that received vehicle. “If we initiate treatment with fluorosamine at peak EAE, we find that while vehicle-treated animals continue to have significant disability, treatment with fluorosamine reduces clinical severity,” said Dr. Yong.

Investigating CSPGs
The current study follows the investigators’ previous examinations of chondroitin sulfate proteoglycans (CSPGs). This class of chemicals includes versican, aggrecan, neurocan, and brevican. In 2001, Sobel and colleagues found neurocan, veriscan, and aggrecan at the edge of an active MS lesion. In other conditions such as traumatic spinal cord injury, CSPGs have been identified as inhibitors of axonal regeneration.

To determine whether CSPGs affect remyelination, Dr. Yong and colleagues investigated a model of demyelination and remyelination in which lysolecithin was injected into an animal’s spinal cord dorsal column. Within three days of demyelination, the researchers found deposition of versican V1 around cells and in acellular areas in the extracellular matrix. In a later study, Dr. Yong and colleagues found that CSPGs were cleared during the process of remyelination that followed lysolecithin-induced demyelination. The group also found that reducing the deposition of CSPGs promoted remyelination.

In 2012, Dr. Yong’s group performed in vitro stripe assays of human oligodendrocyte precursor cells (OPCs). When the human OPCs were plated onto a setup in which stripes had been coated with bovine serum albumin, the OPCs flourished in environments with and without bovine serum albumin. In contrast, OPCs sent few processes into stripes coated with CSPGs. This finding emphasizes “the nonpermissive nature of the CSPGs,” said Dr. Yong.

The Development of Fluorosamine
To reduce the production of CSPGs following injury, Dr. Yong and colleagues designed fluorosamine. They found that peracetylating fluorosamine with many acetyl groups facilitated the compound’s entry into cells. In an in vitro proof-of-concept study, the investigators activated astrocytes with TGF-β to increase their production of CSPGs. When the astrocytes were incubated with peracetylated fluorosamine, the group observed a “robust downregulation of CSPG production by activated astrocytes,” said Dr. Yong.

In an in vivo proof-of-concept study, the researchers induced demyelination in animals by injecting their spinal cords with lysolecithin. After the animals received fluorosamine treatment, the investigators observed significantly reduced expression of versican in the injured spinal cords.

When the researchers stained tissue samples for oligodendrocytes using OLIG2 and GSTπ, they found a greater number of oligodendrocytes within lesions in animals that underwent lysolecithin-induced demyelination and subsequent treatment with fluorosamine than in animals with demyelination that were untreated. In addition, animals that were treated with fluorosamine had more myelinated profiles than untreated animals. A separate study indicated that fluorosamine reduced inflammation in tissue culture by inhibiting macrophage activation.

—Erik Greb

BOSTON—In addition to John Cunningham virus (JCV) index, L-selectin level can help neurologists make treatment decisions for individuals with multiple sclerosis (MS), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The two biomarkers can help neurologists determine which patients are at highest risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML).

More than 40% of patients with MS can be considered at high risk of PML if JCV index alone is taken into account. If only L-selectin level is considered, then between 5% and 15% of patients with MS are at high risk of PML. Taking both JCV index and L-selectin level into account results in a rate of approximately 4% of patients with MS who are at high risk of PML. “That is a further stratification of patients being at risk, with all the advantages and disadvantages that biomarkers and serial assessments would have,” said Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.

Compared with JCV index, L-selectin may have disadvantages as a biomarker. For example, a patient’s JCV index generally is stable, but his or her L-selectin level may fluctuate. Furthermore, it is easier to measure JCV index than L-selectin level, which must be assessed in fragile peripheral blood mononucleated cells.

Yet data indicate that the two biomarkers have comparable sensitivity (98% for JCV index and 91% for L-selectin). An advantage of L-selectin is that it can provide information about all patients, while JCV index only is informative in patients who have not previously had immune suppression, said Dr. Wiendl.

L-Selectin May Indicate PML Risk in Various Disorders
In a 2013 study of patients with MS without previous immune suppression, Plavina et al concluded that individuals with a JCV index greater than 0.9 are at higher risk of developing PML. In the same year, Schwab and colleagues found that patients with MS and an L-selectin value lower than 21.6 are at higher risk of developing PML.

These findings prompted Dr. Wiendl and colleagues to ask whether L-selectin was associated only with natalizumab. They examined 10 patients with HIV who previously had developed PML and found that nine had a low L-selectin value. The group concluded that L-selectin might have a connection to the development of PML in various disorders.

L-Selectin Decreases During Natalizumab Treatment
Dr. Wiendl’s group recruited 2,300 patients with MS to further investigate JCV index and L-selectin. Approximately 55% of the patients had JCV antibodies, and this result is consistent with the literature. Approximately 41% of the cohort had a JCV index greater than 0.9 and were thus at higher risk of developing PML, said Dr. Wiendl.

In analyses of all patients and of only patients who had JCV antibodies, JCV index did not change during treatment with natalizumab. “This [finding] is rather good news for a biomarker because it’s pretty stable all the time,” said Dr. Wiendl. The investigators also found a clear correlation of JCV index with age, “which is a phenomenon that is mainly to be explained by seroconversion.”

The researchers also assessed patients’ L-selectin values. Early in the study, they found that 10 of 11 patients who later developed PML had low L-selectin values. The investigators went on to measure each patient as many as six times. After Dr. Wiendl’s group had screened approximately 800 patients, they calculated that with current protocols and cohorts, L-selectin had a specificity of approximately 89% and a sensitivity of approximately 91% for indicating risk of PML.

By examining the series of measurements for individual patients, the investigators gained additional information about both biomarkers. In one patient who previously had immune suppression and later developed PML, JCV index was low. The result indicates that JCV index is not a reliable indicator of PML risk among patients with previous immune suppression, said Dr. Wiendl.

Another patient had a normal L-selectin value that later decreased, and the patient subsequently developed PML. This patient’s JCV index was consistently high throughout all measurements. One patient with high L-selectin values and high JC index developed PML.

L-Selectin in Clinical Practice
The data indicate that a single measurement of a low L-selectin level confers a higher risk of PML. A patient’s L-selectin level will not necessarily stay low, however; it may recover. This fluctuation underscores the importance of repeated assessments, said Dr. Wiendl. L-selectin is “a dynamic marker that can change,” he added.

In addition, JCV index seems to correlate with L-selectin expression levels. Patients with high JCV index are likely to have a low L-selectin level, but the two biomarkers may not be correlated biologically, said Dr. Wiendl.

Treatment decisions are influenced by unchangeable factors, such as previous immune suppression, and dynamic biomarkers, such as treatment duration and JCV antibody seropositivity. “Then you have two additional parameters that might be helpful for individual treatment decisions: JCV index and L-selectin,” concluded Dr. Wiendl.

—Erik Greb

BOSTON—In addition to John Cunningham virus (JCV) index, L-selectin level can help neurologists make treatment decisions for individuals with multiple sclerosis (MS), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The two biomarkers can help neurologists determine which patients are at highest risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML).

More than 40% of patients with MS can be considered at high risk of PML if JCV index alone is taken into account. If only L-selectin level is considered, then between 5% and 15% of patients with MS are at high risk of PML. Taking both JCV index and L-selectin level into account results in a rate of approximately 4% of patients with MS who are at high risk of PML. “That is a further stratification of patients being at risk, with all the advantages and disadvantages that biomarkers and serial assessments would have,” said Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.

Compared with JCV index, L-selectin may have disadvantages as a biomarker. For example, a patient’s JCV index generally is stable, but his or her L-selectin level may fluctuate. Furthermore, it is easier to measure JCV index than L-selectin level, which must be assessed in fragile peripheral blood mononucleated cells.

Yet data indicate that the two biomarkers have comparable sensitivity (98% for JCV index and 91% for L-selectin). An advantage of L-selectin is that it can provide information about all patients, while JCV index only is informative in patients who have not previously had immune suppression, said Dr. Wiendl.

L-Selectin May Indicate PML Risk in Various Disorders
In a 2013 study of patients with MS without previous immune suppression, Plavina et al concluded that individuals with a JCV index greater than 0.9 are at higher risk of developing PML. In the same year, Schwab and colleagues found that patients with MS and an L-selectin value lower than 21.6 are at higher risk of developing PML.

These findings prompted Dr. Wiendl and colleagues to ask whether L-selectin was associated only with natalizumab. They examined 10 patients with HIV who previously had developed PML and found that nine had a low L-selectin value. The group concluded that L-selectin might have a connection to the development of PML in various disorders.

L-Selectin Decreases During Natalizumab Treatment
Dr. Wiendl’s group recruited 2,300 patients with MS to further investigate JCV index and L-selectin. Approximately 55% of the patients had JCV antibodies, and this result is consistent with the literature. Approximately 41% of the cohort had a JCV index greater than 0.9 and were thus at higher risk of developing PML, said Dr. Wiendl.

In analyses of all patients and of only patients who had JCV antibodies, JCV index did not change during treatment with natalizumab. “This [finding] is rather good news for a biomarker because it’s pretty stable all the time,” said Dr. Wiendl. The investigators also found a clear correlation of JCV index with age, “which is a phenomenon that is mainly to be explained by seroconversion.”

The researchers also assessed patients’ L-selectin values. Early in the study, they found that 10 of 11 patients who later developed PML had low L-selectin values. The investigators went on to measure each patient as many as six times. After Dr. Wiendl’s group had screened approximately 800 patients, they calculated that with current protocols and cohorts, L-selectin had a specificity of approximately 89% and a sensitivity of approximately 91% for indicating risk of PML.

By examining the series of measurements for individual patients, the investigators gained additional information about both biomarkers. In one patient who previously had immune suppression and later developed PML, JCV index was low. The result indicates that JCV index is not a reliable indicator of PML risk among patients with previous immune suppression, said Dr. Wiendl.

Another patient had a normal L-selectin value that later decreased, and the patient subsequently developed PML. This patient’s JCV index was consistently high throughout all measurements. One patient with high L-selectin values and high JC index developed PML.

L-Selectin in Clinical Practice
The data indicate that a single measurement of a low L-selectin level confers a higher risk of PML. A patient’s L-selectin level will not necessarily stay low, however; it may recover. This fluctuation underscores the importance of repeated assessments, said Dr. Wiendl. L-selectin is “a dynamic marker that can change,” he added.

In addition, JCV index seems to correlate with L-selectin expression levels. Patients with high JCV index are likely to have a low L-selectin level, but the two biomarkers may not be correlated biologically, said Dr. Wiendl.

Treatment decisions are influenced by unchangeable factors, such as previous immune suppression, and dynamic biomarkers, such as treatment duration and JCV antibody seropositivity. “Then you have two additional parameters that might be helpful for individual treatment decisions: JCV index and L-selectin,” concluded Dr. Wiendl.

—Erik Greb

BOSTON—In addition to John Cunningham virus (JCV) index, L-selectin level can help neurologists make treatment decisions for individuals with multiple sclerosis (MS), according to research presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting. The two biomarkers can help neurologists determine which patients are at highest risk of natalizumab-associated progressive multifocal leukoencephalopathy (PML).

More than 40% of patients with MS can be considered at high risk of PML if JCV index alone is taken into account. If only L-selectin level is considered, then between 5% and 15% of patients with MS are at high risk of PML. Taking both JCV index and L-selectin level into account results in a rate of approximately 4% of patients with MS who are at high risk of PML. “That is a further stratification of patients being at risk, with all the advantages and disadvantages that biomarkers and serial assessments would have,” said Heinz Wiendl, MD, Professor of Neurology at the University of Münster in Germany.

Compared with JCV index, L-selectin may have disadvantages as a biomarker. For example, a patient’s JCV index generally is stable, but his or her L-selectin level may fluctuate. Furthermore, it is easier to measure JCV index than L-selectin level, which must be assessed in fragile peripheral blood mononucleated cells.

Yet data indicate that the two biomarkers have comparable sensitivity (98% for JCV index and 91% for L-selectin). An advantage of L-selectin is that it can provide information about all patients, while JCV index only is informative in patients who have not previously had immune suppression, said Dr. Wiendl.

L-Selectin May Indicate PML Risk in Various Disorders
In a 2013 study of patients with MS without previous immune suppression, Plavina et al concluded that individuals with a JCV index greater than 0.9 are at higher risk of developing PML. In the same year, Schwab and colleagues found that patients with MS and an L-selectin value lower than 21.6 are at higher risk of developing PML.

These findings prompted Dr. Wiendl and colleagues to ask whether L-selectin was associated only with natalizumab. They examined 10 patients with HIV who previously had developed PML and found that nine had a low L-selectin value. The group concluded that L-selectin might have a connection to the development of PML in various disorders.

L-Selectin Decreases During Natalizumab Treatment
Dr. Wiendl’s group recruited 2,300 patients with MS to further investigate JCV index and L-selectin. Approximately 55% of the patients had JCV antibodies, and this result is consistent with the literature. Approximately 41% of the cohort had a JCV index greater than 0.9 and were thus at higher risk of developing PML, said Dr. Wiendl.

In analyses of all patients and of only patients who had JCV antibodies, JCV index did not change during treatment with natalizumab. “This [finding] is rather good news for a biomarker because it’s pretty stable all the time,” said Dr. Wiendl. The investigators also found a clear correlation of JCV index with age, “which is a phenomenon that is mainly to be explained by seroconversion.”

The researchers also assessed patients’ L-selectin values. Early in the study, they found that 10 of 11 patients who later developed PML had low L-selectin values. The investigators went on to measure each patient as many as six times. After Dr. Wiendl’s group had screened approximately 800 patients, they calculated that with current protocols and cohorts, L-selectin had a specificity of approximately 89% and a sensitivity of approximately 91% for indicating risk of PML.

By examining the series of measurements for individual patients, the investigators gained additional information about both biomarkers. In one patient who previously had immune suppression and later developed PML, JCV index was low. The result indicates that JCV index is not a reliable indicator of PML risk among patients with previous immune suppression, said Dr. Wiendl.

Another patient had a normal L-selectin value that later decreased, and the patient subsequently developed PML. This patient’s JCV index was consistently high throughout all measurements. One patient with high L-selectin values and high JC index developed PML.

L-Selectin in Clinical Practice
The data indicate that a single measurement of a low L-selectin level confers a higher risk of PML. A patient’s L-selectin level will not necessarily stay low, however; it may recover. This fluctuation underscores the importance of repeated assessments, said Dr. Wiendl. L-selectin is “a dynamic marker that can change,” he added.

In addition, JCV index seems to correlate with L-selectin expression levels. Patients with high JCV index are likely to have a low L-selectin level, but the two biomarkers may not be correlated biologically, said Dr. Wiendl.

Treatment decisions are influenced by unchangeable factors, such as previous immune suppression, and dynamic biomarkers, such as treatment duration and JCV antibody seropositivity. “Then you have two additional parameters that might be helpful for individual treatment decisions: JCV index and L-selectin,” concluded Dr. Wiendl.

—Erik Greb

BOSTON—Radiologically isolated syndrome (RIS) may be the first visible manifestation of multiple sclerosis (MS), according to an overview that was presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Not all neurologists accept RIS as a valid and distinct entity, however. Providing a firm, scientific basis for the diagnosis may require improved characterization of the syndrome and the lesions that define it.

An important question for researchers to answer is whether MS, similar to diseases such as high blood pressure, high cholesterol, and diabetes, should be treated early (eg, at RIS onset) to improve disability over time, said Darin T. Okuda, MD, Associate Professor of Neurology and Neurotherapeutics at the University of Texas Southwestern in Dallas. “We definitely need more scientific studies to answer this very important question: Would earlier treatment result in better long-term outcomes for patients?”

What Is RIS? A diagnosis of RIS may result from an MRI ordered to investigate a complaint unrelated to MS. “For the most part, these are individuals who were being worked up for migraine headache complaints, cerebrovascular accidents, [and] post-traumatic events,” said Dr. Okuda. A neurologist may diagnose RIS when the MRI reveals features within the brain and spinal cord that strongly suggest MS. Such features include periventricular, ovoid, circumscribed lesions within the cervical and thoracic spinal cord.

In addition, to diagnose RIS, a neurologist must confirm that the patient has never had clinical symptoms of MS. “We do our best to ensure that we are not missing another condition or disease process that could better explain why these structural anomalies are observed,” said Dr. Okuda.

The literature appears to provide evidence for asymptomatic MS. “Great scientific data support the presence of incidental anomalies [and] asymptomatic anomalies within the CNS from sporadic and familial MS cases,” said Dr. Okuda. Large collections of postmortem cases have identified and validated demyelinating changes within brain and spinal cord tissue, and researchers have described brain changes that are highly suggestive of MS. “Healthy subjects are definitely a group of interest because they appear asymptomatic and clearly possess features consistent with demyelinating disease,” said Dr. Okuda.

Skepticism About RIS
Neurologists have presented several arguments that RIS is not a distinct entity. One argument is that patients diagnosed with RIS have cryptogenic white matter changes but not MS. Many patients with RIS have changes in a brain region that MS does not typically affect, such as the subcortical or frontal region.

Another argument is that the patients, knowingly or not, have had clinical symptoms of MS. This objection often is directed against clinically isolated syndrome, too, said Dr. Okuda. Furthermore, some neurologists suggest that RIS is actually MS. The literature, however, appears to lend support to RIS as a diagnosis. Many MRI studies focusing on at-risk groups indicate the existence of presymptomatic disease, and recent scientific evidence suggests that deep gray matter volume changes may be present before the first clinical attack suggestive of MS, said Dr. Okuda.

Conventional Imaging May Lead to Overdiagnosis
Neurologists now use conventional imaging technology more often than novel techniques, but this tendency may result in the overdiagnosis of RIS, said Dr. Okuda. With conventional imaging, lesions may appear to be typical of MS when they are unrelated to the disease.

Future imaging efforts could prevent such mistakes. Newer techniques enable neurologists to see whether blood vessels traverse the lesions, and this feature is characteristic of MS-related changes, said Dr. Okuda. A preponderance of these features on brain MRI suggests that MS, rather than an unknown cause, is responsible for the findings. High-resolution imaging and qualitative imaging studies also could improve the diagnosis of RIS.

Treatment of RIS
No scientific data currently address the question of whether to treat a patient with RIS. One common reason that neurologists choose treatment is that the patient’s MRI scan has evolved and revealed more changes (eg, contrast enhancement or additional lesions) that are consistent with MS. Neurologists also may decide to treat RIS if the patient’s MRI has particularly negative findings such as tumefactive-like lesions, lesions involving the gray and white matter, or signs of old disease. Contrast enhancement within a specific brain region for an individual with features typical of MS also prompts some neurologists to initiate treatment.

Nevertheless, the effects of treating RIS with disease-modifying therapy (DMT) are unknown. “We need to treat these individuals under a controlled environment” in a prospective study, said Dr. Okuda. The RIS Consortium recently formed a strategic research alliance with Biogen Idec to assess the effect of dimethyl fumarate on extending the time to a first neurologic event associated with CNS demyelination. This study within the US will begin enrollment during the last quarter of 2014.

One-Third of Patients With RIS Had an Attack
Dr. Okuda and colleagues performed a retrospective analysis of individuals with RIS in the United States, Spain, France, Italy, and Turkey. The researchers’ goal was to collect cases and assess for risk factors for first symptom onset. They identified 451 subjects with RIS, the majority of whom were from the US. Most patients were young (mean age, 37.2), Caucasian, and female.

The most common reason the patients underwent MRI was for headache evaluation. Approximately 10% of subjects had a family history of MS, and about 65% had an abnormal CSF profile. These results indicate the specificity of the criteria that the researchers used to identify subjects­­, said Dr. Okuda. Approximately 17% of patients were exposed to a DMT before first symptom onset.

During the five-year study period, 34% of the cohort had a first attack suggestive of MS. This result “provided further validation that asymptomatic MS exists,” said Dr. Okuda. The investigators identified spinal cord lesions within the cervical or thoracic region, age younger than 37, and male sex as risk factors for a first attack. Having more than one risk factor was associated with a greater risk than having only one risk factor.

Among patients who had a first attack, 11% were identified with a primary progressive MS phenotype. This finding provides evidence for an asymptomatic form of progressive MS, said Dr. Okuda. In addition, for those subjects with an initial MRI study performed after 2008 that revealed anomalies suggestive of MS, 40% demonstrated worsening on MRI and had an increased risk for a seminal clinical event, but further scientific efforts would be needed to confirm these data, said Dr. Okuda.

—Erik Greb

BOSTON—Radiologically isolated syndrome (RIS) may be the first visible manifestation of multiple sclerosis (MS), according to an overview that was presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Not all neurologists accept RIS as a valid and distinct entity, however. Providing a firm, scientific basis for the diagnosis may require improved characterization of the syndrome and the lesions that define it.

An important question for researchers to answer is whether MS, similar to diseases such as high blood pressure, high cholesterol, and diabetes, should be treated early (eg, at RIS onset) to improve disability over time, said Darin T. Okuda, MD, Associate Professor of Neurology and Neurotherapeutics at the University of Texas Southwestern in Dallas. “We definitely need more scientific studies to answer this very important question: Would earlier treatment result in better long-term outcomes for patients?”

What Is RIS? A diagnosis of RIS may result from an MRI ordered to investigate a complaint unrelated to MS. “For the most part, these are individuals who were being worked up for migraine headache complaints, cerebrovascular accidents, [and] post-traumatic events,” said Dr. Okuda. A neurologist may diagnose RIS when the MRI reveals features within the brain and spinal cord that strongly suggest MS. Such features include periventricular, ovoid, circumscribed lesions within the cervical and thoracic spinal cord.

In addition, to diagnose RIS, a neurologist must confirm that the patient has never had clinical symptoms of MS. “We do our best to ensure that we are not missing another condition or disease process that could better explain why these structural anomalies are observed,” said Dr. Okuda.

The literature appears to provide evidence for asymptomatic MS. “Great scientific data support the presence of incidental anomalies [and] asymptomatic anomalies within the CNS from sporadic and familial MS cases,” said Dr. Okuda. Large collections of postmortem cases have identified and validated demyelinating changes within brain and spinal cord tissue, and researchers have described brain changes that are highly suggestive of MS. “Healthy subjects are definitely a group of interest because they appear asymptomatic and clearly possess features consistent with demyelinating disease,” said Dr. Okuda.

Skepticism About RIS
Neurologists have presented several arguments that RIS is not a distinct entity. One argument is that patients diagnosed with RIS have cryptogenic white matter changes but not MS. Many patients with RIS have changes in a brain region that MS does not typically affect, such as the subcortical or frontal region.

Another argument is that the patients, knowingly or not, have had clinical symptoms of MS. This objection often is directed against clinically isolated syndrome, too, said Dr. Okuda. Furthermore, some neurologists suggest that RIS is actually MS. The literature, however, appears to lend support to RIS as a diagnosis. Many MRI studies focusing on at-risk groups indicate the existence of presymptomatic disease, and recent scientific evidence suggests that deep gray matter volume changes may be present before the first clinical attack suggestive of MS, said Dr. Okuda.

Conventional Imaging May Lead to Overdiagnosis
Neurologists now use conventional imaging technology more often than novel techniques, but this tendency may result in the overdiagnosis of RIS, said Dr. Okuda. With conventional imaging, lesions may appear to be typical of MS when they are unrelated to the disease.

Future imaging efforts could prevent such mistakes. Newer techniques enable neurologists to see whether blood vessels traverse the lesions, and this feature is characteristic of MS-related changes, said Dr. Okuda. A preponderance of these features on brain MRI suggests that MS, rather than an unknown cause, is responsible for the findings. High-resolution imaging and qualitative imaging studies also could improve the diagnosis of RIS.

Treatment of RIS
No scientific data currently address the question of whether to treat a patient with RIS. One common reason that neurologists choose treatment is that the patient’s MRI scan has evolved and revealed more changes (eg, contrast enhancement or additional lesions) that are consistent with MS. Neurologists also may decide to treat RIS if the patient’s MRI has particularly negative findings such as tumefactive-like lesions, lesions involving the gray and white matter, or signs of old disease. Contrast enhancement within a specific brain region for an individual with features typical of MS also prompts some neurologists to initiate treatment.

Nevertheless, the effects of treating RIS with disease-modifying therapy (DMT) are unknown. “We need to treat these individuals under a controlled environment” in a prospective study, said Dr. Okuda. The RIS Consortium recently formed a strategic research alliance with Biogen Idec to assess the effect of dimethyl fumarate on extending the time to a first neurologic event associated with CNS demyelination. This study within the US will begin enrollment during the last quarter of 2014.

One-Third of Patients With RIS Had an Attack
Dr. Okuda and colleagues performed a retrospective analysis of individuals with RIS in the United States, Spain, France, Italy, and Turkey. The researchers’ goal was to collect cases and assess for risk factors for first symptom onset. They identified 451 subjects with RIS, the majority of whom were from the US. Most patients were young (mean age, 37.2), Caucasian, and female.

The most common reason the patients underwent MRI was for headache evaluation. Approximately 10% of subjects had a family history of MS, and about 65% had an abnormal CSF profile. These results indicate the specificity of the criteria that the researchers used to identify subjects­­, said Dr. Okuda. Approximately 17% of patients were exposed to a DMT before first symptom onset.

During the five-year study period, 34% of the cohort had a first attack suggestive of MS. This result “provided further validation that asymptomatic MS exists,” said Dr. Okuda. The investigators identified spinal cord lesions within the cervical or thoracic region, age younger than 37, and male sex as risk factors for a first attack. Having more than one risk factor was associated with a greater risk than having only one risk factor.

Among patients who had a first attack, 11% were identified with a primary progressive MS phenotype. This finding provides evidence for an asymptomatic form of progressive MS, said Dr. Okuda. In addition, for those subjects with an initial MRI study performed after 2008 that revealed anomalies suggestive of MS, 40% demonstrated worsening on MRI and had an increased risk for a seminal clinical event, but further scientific efforts would be needed to confirm these data, said Dr. Okuda.

—Erik Greb

BOSTON—Radiologically isolated syndrome (RIS) may be the first visible manifestation of multiple sclerosis (MS), according to an overview that was presented at the 2014 Joint ACTRIMS–ECTRIMS Meeting.

Not all neurologists accept RIS as a valid and distinct entity, however. Providing a firm, scientific basis for the diagnosis may require improved characterization of the syndrome and the lesions that define it.

An important question for researchers to answer is whether MS, similar to diseases such as high blood pressure, high cholesterol, and diabetes, should be treated early (eg, at RIS onset) to improve disability over time, said Darin T. Okuda, MD, Associate Professor of Neurology and Neurotherapeutics at the University of Texas Southwestern in Dallas. “We definitely need more scientific studies to answer this very important question: Would earlier treatment result in better long-term outcomes for patients?”

What Is RIS? A diagnosis of RIS may result from an MRI ordered to investigate a complaint unrelated to MS. “For the most part, these are individuals who were being worked up for migraine headache complaints, cerebrovascular accidents, [and] post-traumatic events,” said Dr. Okuda. A neurologist may diagnose RIS when the MRI reveals features within the brain and spinal cord that strongly suggest MS. Such features include periventricular, ovoid, circumscribed lesions within the cervical and thoracic spinal cord.

In addition, to diagnose RIS, a neurologist must confirm that the patient has never had clinical symptoms of MS. “We do our best to ensure that we are not missing another condition or disease process that could better explain why these structural anomalies are observed,” said Dr. Okuda.

The literature appears to provide evidence for asymptomatic MS. “Great scientific data support the presence of incidental anomalies [and] asymptomatic anomalies within the CNS from sporadic and familial MS cases,” said Dr. Okuda. Large collections of postmortem cases have identified and validated demyelinating changes within brain and spinal cord tissue, and researchers have described brain changes that are highly suggestive of MS. “Healthy subjects are definitely a group of interest because they appear asymptomatic and clearly possess features consistent with demyelinating disease,” said Dr. Okuda.

Skepticism About RIS
Neurologists have presented several arguments that RIS is not a distinct entity. One argument is that patients diagnosed with RIS have cryptogenic white matter changes but not MS. Many patients with RIS have changes in a brain region that MS does not typically affect, such as the subcortical or frontal region.

Another argument is that the patients, knowingly or not, have had clinical symptoms of MS. This objection often is directed against clinically isolated syndrome, too, said Dr. Okuda. Furthermore, some neurologists suggest that RIS is actually MS. The literature, however, appears to lend support to RIS as a diagnosis. Many MRI studies focusing on at-risk groups indicate the existence of presymptomatic disease, and recent scientific evidence suggests that deep gray matter volume changes may be present before the first clinical attack suggestive of MS, said Dr. Okuda.

Conventional Imaging May Lead to Overdiagnosis
Neurologists now use conventional imaging technology more often than novel techniques, but this tendency may result in the overdiagnosis of RIS, said Dr. Okuda. With conventional imaging, lesions may appear to be typical of MS when they are unrelated to the disease.

Future imaging efforts could prevent such mistakes. Newer techniques enable neurologists to see whether blood vessels traverse the lesions, and this feature is characteristic of MS-related changes, said Dr. Okuda. A preponderance of these features on brain MRI suggests that MS, rather than an unknown cause, is responsible for the findings. High-resolution imaging and qualitative imaging studies also could improve the diagnosis of RIS.

Treatment of RIS
No scientific data currently address the question of whether to treat a patient with RIS. One common reason that neurologists choose treatment is that the patient’s MRI scan has evolved and revealed more changes (eg, contrast enhancement or additional lesions) that are consistent with MS. Neurologists also may decide to treat RIS if the patient’s MRI has particularly negative findings such as tumefactive-like lesions, lesions involving the gray and white matter, or signs of old disease. Contrast enhancement within a specific brain region for an individual with features typical of MS also prompts some neurologists to initiate treatment.

Nevertheless, the effects of treating RIS with disease-modifying therapy (DMT) are unknown. “We need to treat these individuals under a controlled environment” in a prospective study, said Dr. Okuda. The RIS Consortium recently formed a strategic research alliance with Biogen Idec to assess the effect of dimethyl fumarate on extending the time to a first neurologic event associated with CNS demyelination. This study within the US will begin enrollment during the last quarter of 2014.

One-Third of Patients With RIS Had an Attack
Dr. Okuda and colleagues performed a retrospective analysis of individuals with RIS in the United States, Spain, France, Italy, and Turkey. The researchers’ goal was to collect cases and assess for risk factors for first symptom onset. They identified 451 subjects with RIS, the majority of whom were from the US. Most patients were young (mean age, 37.2), Caucasian, and female.

The most common reason the patients underwent MRI was for headache evaluation. Approximately 10% of subjects had a family history of MS, and about 65% had an abnormal CSF profile. These results indicate the specificity of the criteria that the researchers used to identify subjects­­, said Dr. Okuda. Approximately 17% of patients were exposed to a DMT before first symptom onset.

During the five-year study period, 34% of the cohort had a first attack suggestive of MS. This result “provided further validation that asymptomatic MS exists,” said Dr. Okuda. The investigators identified spinal cord lesions within the cervical or thoracic region, age younger than 37, and male sex as risk factors for a first attack. Having more than one risk factor was associated with a greater risk than having only one risk factor.

Among patients who had a first attack, 11% were identified with a primary progressive MS phenotype. This finding provides evidence for an asymptomatic form of progressive MS, said Dr. Okuda. In addition, for those subjects with an initial MRI study performed after 2008 that revealed anomalies suggestive of MS, 40% demonstrated worsening on MRI and had an increased risk for a seminal clinical event, but further scientific efforts would be needed to confirm these data, said Dr. Okuda.

—Erik Greb

BOSTON—More than 45 new multiple sclerosis (MS) susceptibility variants were reported by researchers.

“We now present a comprehensive view of MS genetic susceptibility and provide a detailed map of proximal biologic effects that identify new molecular pathways involved in the transition from health to MS,” said Philip Laurence De Jager, MD, PhD, Assistant Professor, Harvard Medical School in Boston, on behalf of the International MS Genetics Consortium.

To identify MS susceptibility associations outside the validated MS susceptibility loci and uncover new biologic processes that drive the onset of MS, the researchers conducted a genomewide discovery study of approximately eight million single-nucleotide polymorphisms (SNPs) in each of 14,802 MS cases and 26,703 controls. This step was followed by a deep replication study of more than 80,000 SNPs in more than 19,217 MS cases and 17,842 controls. The 4,716 SNPs with a P value of less than 0.05 in the discovery study were included in the present study. Functional evaluations of the results were conducted using DEPICT for pathway analysis, as well as analyses of immune cell RNA expression data from ImmVar and reference epigenomic maps from the Epigenome Roadmap and ENCODE projects.

At the end of the replication study, more than 45 new susceptibility variants were identified, with 10 major histocompatibility complex (MHC) and more than 150 non-MHC SNPs meeting a threshold of genomewide significance. The depth of the replication effort identified multiple independent effects in many regions that were previously unresolvable. For example, the EVI5 region has as many as four independent susceptibility variants.

“Uncovering this multiplicity of associations in certain regions is critical to our efforts to model the biologic consequences of MS susceptibility variants and to develop predictive algorithms,” Dr. De Jager said. “With more than 150 independent susceptibility effects and a high resolution analysis of each locus in hand, we have created a reference map of MS susceptibility and now turn to the task of understanding the biology of MS susceptibility.

“With the new MS map and multiple approaches to epigenomic annotation and functional evaluations, it is clear that non-TH1/Th17/Treg processes are important in the onset of MS,” he continued. “Myeloid, NK, and CD8 cells are now implicated, and B and dendritic cell functions are suggested to be altered by MS variants.”

Leveraging RNA data from 405 subjects with purified CD4 T and monocytes, 29% of MS variants with RNA effects are unique to monocytes, which is now the same proportion as for T cells (29%). Pathway analyses highlighted an enrichment of NK and B cell activation molecular networks in addition to T cell effects.

—Glenn S. Williams

Investigational Oral Drug Reduces Disease Activity in Relapsing-Remitting MS
An oral, selective sphingosine 1-phosphate 1 receptor modulator appears to reduce MRI measures of disease activity in patients with relapsing-remitting multiple sclerosis (MS), according to data presented. The drug, RPC1063, may be safe and tolerable for these patients.

Data are from the international, combined phase II/III RADIANCE trial. Jeffrey Cohen, MD, Director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research in Cleveland, and colleagues randomized 258 patients with relapsing-remitting MS. A total of 87 participants received a low dose (0.5 mg) of RPC1063, 83 participants received a high dose (1.0 mg) of RPC1063, and 88 participants received placebo for 24 weeks.

The trial’s primary end point was the cumulative number of total gadolinium-enhancing lesions on MRI at weeks 12, 16, 20, and 24. Key secondary end points included the number of gadolinium-enhancing lesions at week 24, the cumulative number of new or enlarging T2 lesions from weeks 12 to 24, and annualized relapse rate.

The researchers assessed safety using vital signs, laboratory tests, ECG, Holter monitoring, pulmonary function test, optical coherence tomography, and adverse events. Patients were titrated to their assigned doses during one week to mitigate the first doses’ effects on heart rate.

Approximately 98% of patients completed the trial. The cumulative number of gadolinium-enhancing lesions from weeks 12 to 24 was reduced by 86% in both treatment arms, compared with placebo. The numbers of gadolinium-enhancing lesions at week 24 were significantly reduced by 91% in the low-dose group and by 94% in the high-dose group, compared with placebo. The cumulative number of new or enlarging T2 lesions from weeks 12 to 24 was reduced by 84% in the low-dose group and by 91% in the high-dose group. The researchers observed a favorable trend toward a reduction in annualized relapse rate among treated patients, compared with controls.

The adverse event profiles were similar between groups. The most common adverse events in the treated groups, compared with placebo, were nasopharyngitis (9.4% vs 13.6%), headache (4.7% vs 9.1%), and urinary tract infection (4.7% vs 2.3%). During the first six hours after the first dose of RPC1063, maximum reductions in mean hourly heart rate were < 2 bpm from baseline, and no patient had a minimum hourly heart rate < 45 bpm. The investigators did not observe any notable cardiac, pulmonary, ophthalmologic, or malignancy adverse events.

“Both doses of RPC1063 demonstrated large, significant, and consistent reductions of all MRI measures of MS disease activity,” said Dr. Cohen. “The tolerability and safety results suggest a favorable risk–benefit profile of RPC1063 in the treatment of relapsing-remitting MS. These results support the ongoing phase III portion of the RADIANCE trial of RPC1063 vs interferon beta-1a in relapsing-remitting MS,” he concluded.

—Erik Greb

Improved Adherence to Disease-Modifying Therapy Reduces Health Care Resource Use and Medical Costs
Improved adherence to disease-modifying therapy (DMT) is associated with lower medical and indirect costs, reduced work-loss days, and decreased inpatient stays and emergency visits for patients with multiple sclerosis (MS), investigators reported.

According to published estimates, real-world adherence to DMTs in MS ranges from 41% to 88%, and higher adherence is associated with lower rates of relapse and lower costs. Sander Yermakov, from the Analysis Group in Boston, and researchers from Biogen Idec in Cambridge, Massachusetts, sought to estimate the effect of adherence to DMTs in health care resource use and cost outcomes in patients with MS and to model the impact of improving adherence on these outcomes.

A retrospective analysis was conducted using the OptumHealth Reporting & Insights employer claims database, which contains information on medical and pharmacy claims for more than 18 million beneficiaries in the US, as well as disability claims and salary information in a subset of approximately 4.2 million employees. Employed patients with two or more MS diagnoses (ICD-9-CM 340) initiating DMT from January 2, 2002, through March 31, 2012, were included in the analysis.

Direct medical costs (paid amounts to providers for services or drugs, excluding payments for DMTs), indirect costs (disability payments to employees and work-loss costs to employers), and resource use were analyzed in the six months prior to initiation of any DMT (baseline period) and for three years after initiation (follow-up period). Adherence to any DMT was defined as the proportion of days covered (PDC) and measured using the percentage of days in each follow-up period during which the patient had one or more MS DMT available.

Multivariate regression analyses were used to estimate the effect of PDC on follow-up period outcomes, controlling for baseline characteristics. The estimated model was used to predict the change in use and costs associated with a 10% improvement in PDC.

A total of 1,538 patients met the selection criteria (baseline age, 43.6; 63% female). PDC had a statistically significant effect on direct medical and indirect work productivity costs, work-loss days, and likelihood of an inpatient stay or emergency visit at one-, two-, and three-year follow-up. A 10% improvement in PDC was estimated to reduce direct costs by 4%, indirect costs by 3% to 4%, work-loss days by 3% to 7%, likelihood of an inpatient stay by 13% to 19%, and likelihood of an emergency visit by 8% to 19%, depending on the follow-up period.

The impact on the likelihood of an inpatient stay or emergency visit increased with the length of the follow-up period. In the first year, the decrease in direct costs associated with a 10% improvement in adherence was greater for patients with PDC of 0.8 or higher (10%), men (6%), and patients not on disability in the baseline period.

—Glenn S. Williams

Equivalence Demonstrated by a Generic Version of Glatiramer Acetate
Results of the randomized, double-blind GATE trial indicate that generic glatiramer acetate is equivalent to branded Copaxone in reducing the number of gadolinium-enhancing lesions, a clinically relevant end point in relapsing-remitting multiple sclerosis (RRMS). Other efficacy outcomes, safety, and tolerability also were comparable.

“This is the first generic glatiramer acetate with an efficacy and safety profile demonstrated to be equivalent to the currently marketed product,” said Jeffrey A. Cohen, MD, Director of the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, on behalf of the GATE Study Group.

“Generic alternatives to the currently approved therapies for RRMS are needed,” Dr. Cohen said. But because glatiramer acetate is a complex polypeptide mixture that precludes pharmacokinetic comparison, a generic version needs to demonstrate equivalence in efficacy and safety. The GATE trial aimed to show that generic glatiramer acetate was equivalent to Copaxone (Teva Pharmaceuticals; North Wales, Pennsylvania), as measured by MRI and clinical end points, safety, and tolerability in RRMS.

Patients with ambulatory RRMS (ages 18 to 55) with one or more relapse in the year prior to screening and one to 15 gadolinium-enhancing brain lesions were randomized in a 4.3:4.3:1 fashion in a multicenter, double-blind, placebo-controlled trial to receive 20 mg of generic glatiramer acetate, 20 mg of Copaxone, or placebo by daily subcutaneous injection for nine months. The primary end point was combined number of gadolinium-enhancing lesions over months seven, eight, and nine. Additional efficacy end points included other MRI parameters, annualized relapse rate, Expanded Disability Status Scale (EDSS) score, and freedom from disease activity. Safety and tolerability were assessed through monitoring of adverse events, injection site reactions, and routine blood laboratory tests.

A total of 794 patients were randomized and treated with generic glatiramer acetate (n = 353), Copaxone (n = 357), or placebo (n = 84). Of these, 735 patients (92.5%) completed the nine-month double-blind treatment period. The estimated geometric mean numbers of gadolinium-enhancing lesions were 0.42 for generic glatiramer acetate and 0.39 for Copaxone, resulting in an estimated generic/brand lesion ratio of 1.097 with a 95% confidence interval of 0.884 to 1.362, which is within the predefined equivalence margin.

The estimated geometric mean number of gadolinium-enhancing lesions for both the generic and brand drug groups was lower than for the placebo group, confirming assay sensitivity. Annualized relapse rates were 0.31 for generic glatiramer acetate, 0.41 for Copaxone, and 0.39 for placebo. Comparable proportions of patients treated with the generic and branded drug were free from disease activity. EDSS was stable in all three groups. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the two treatment groups.

The generic version of glatiramer acetate is being developed by Synthon Biopharmaceuticals BV (Nijmegen, the Netherlands).

—Glenn S. Williams

Does Brain Reserve Protect Against Physical Disability in MS?
Patients with multiple sclerosis (MS) who have larger maximal lifetime brain growth may have less physical disability, according to researchers. Larger maximal lifetime brain growth may help preserve patients’ ambulation and fine motor function.

“Clinical consideration of maximal lifetime brain growth … may help identify patients with MS at highest risk for future physical disability,” said James F. Sumowski, PhD, Senior Research Scientist of Neuropsychology and Neuroscience Research at the Kessler Foundation Research Center in West Orange, New Jersey. “At-risk patients can be enrolled in early intervention treatments or research on such treatments.”

Dr. Sumowski and colleagues studied 352 patients with MS, including 255 people with relapsing-remitting MS and 97 people with secondary progressive MS. The researchers assessed participants’ disease burden using high-resolution, 3-D, T1 fast field echo. They used software to normalize patients’ total brain, gray matter, white matter, deep gray matter, and thalamus volumes. The researchers also used dual-echo turbo spin echo to quantify T2 lesion volume. Dr. Sumowski’s group estimated maximal lifetime brain growth with SIENAX v-scaling factor (adjusted for gender), a proxy for intracranial volume.

In addition, the investigators assessed 168 participants’ ambulation with the 25-Foot Walk. Participants who used assistive devices for walking were excluded. Fine motor function was assessed with the Nine-Hole Peg Test (in 323 patients) and Finger Tapping Test (in 330 patients). Cognitive status was assessed in 333 patients with the Paced Auditory Serial Addition Test-3 (PASAT-3).

Dr. Sumowski and colleagues found that maximal lifetime brain growth significantly predicted pyramidal and cerebellar function. Maximal lifetime brain growth accounted for the variance between patients in physical disability, as measured by the Finger Tapping Test. People with larger maximal lifetime brain growth performed better on that test. Disability was worse in people with smaller maximal lifetime brain growth, and the relationship did not change when the researchers controlled for demographics and deep gray matter atrophy.

The investigators found a similar relationship for cerebellar function. Participants with larger maximal lifetime brain growth had less disability and cerebellar dysfunction, even when the researchers controlled for demographics and disease burden. Patients with larger maximal lifetime brain growth completed the 25-Foot Walk more quickly, which indicated that they had less disability.

The researchers did not find a relationship between maximal lifetime brain growth and other functional systems, such as brainstem, visual, motor sensory, and bladder function.

—Erik Greb

BOSTON—More than 45 new multiple sclerosis (MS) susceptibility variants were reported by researchers.

“We now present a comprehensive view of MS genetic susceptibility and provide a detailed map of proximal biologic effects that identify new molecular pathways involved in the transition from health to MS,” said Philip Laurence De Jager, MD, PhD, Assistant Professor, Harvard Medical School in Boston, on behalf of the International MS Genetics Consortium.

To identify MS susceptibility associations outside the validated MS susceptibility loci and uncover new biologic processes that drive the onset of MS, the researchers conducted a genomewide discovery study of approximately eight million single-nucleotide polymorphisms (SNPs) in each of 14,802 MS cases and 26,703 controls. This step was followed by a deep replication study of more than 80,000 SNPs in more than 19,217 MS cases and 17,842 controls. The 4,716 SNPs with a P value of less than 0.05 in the discovery study were included in the present study. Functional evaluations of the results were conducted using DEPICT for pathway analysis, as well as analyses of immune cell RNA expression data from ImmVar and reference epigenomic maps from the Epigenome Roadmap and ENCODE projects.

At the end of the replication study, more than 45 new susceptibility variants were identified, with 10 major histocompatibility complex (MHC) and more than 150 non-MHC SNPs meeting a threshold of genomewide significance. The depth of the replication effort identified multiple independent effects in many regions that were previously unresolvable. For example, the EVI5 region has as many as four independent susceptibility variants.

“Uncovering this multiplicity of associations in certain regions is critical to our efforts to model the biologic consequences of MS susceptibility variants and to develop predictive algorithms,” Dr. De Jager said. “With more than 150 independent susceptibility effects and a high resolution analysis of each locus in hand, we have created a reference map of MS susceptibility and now turn to the task of understanding the biology of MS susceptibility.

“With the new MS map and multiple approaches to epigenomic annotation and functional evaluations, it is clear that non-TH1/Th17/Treg processes are important in the onset of MS,” he continued. “Myeloid, NK, and CD8 cells are now implicated, and B and dendritic cell functions are suggested to be altered by MS variants.”

Leveraging RNA data from 405 subjects with purified CD4 T and monocytes, 29% of MS variants with RNA effects are unique to monocytes, which is now the same proportion as for T cells (29%). Pathway analyses highlighted an enrichment of NK and B cell activation molecular networks in addition to T cell effects.

—Glenn S. Williams

Investigational Oral Drug Reduces Disease Activity in Relapsing-Remitting MS
An oral, selective sphingosine 1-phosphate 1 receptor modulator appears to reduce MRI measures of disease activity in patients with relapsing-remitting multiple sclerosis (MS), according to data presented. The drug, RPC1063, may be safe and tolerable for these patients.

Data are from the international, combined phase II/III RADIANCE trial. Jeffrey Cohen, MD, Director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research in Cleveland, and colleagues randomized 258 patients with relapsing-remitting MS. A total of 87 participants received a low dose (0.5 mg) of RPC1063, 83 participants received a high dose (1.0 mg) of RPC1063, and 88 participants received placebo for 24 weeks.

The trial’s primary end point was the cumulative number of total gadolinium-enhancing lesions on MRI at weeks 12, 16, 20, and 24. Key secondary end points included the number of gadolinium-enhancing lesions at week 24, the cumulative number of new or enlarging T2 lesions from weeks 12 to 24, and annualized relapse rate.

The researchers assessed safety using vital signs, laboratory tests, ECG, Holter monitoring, pulmonary function test, optical coherence tomography, and adverse events. Patients were titrated to their assigned doses during one week to mitigate the first doses’ effects on heart rate.

Approximately 98% of patients completed the trial. The cumulative number of gadolinium-enhancing lesions from weeks 12 to 24 was reduced by 86% in both treatment arms, compared with placebo. The numbers of gadolinium-enhancing lesions at week 24 were significantly reduced by 91% in the low-dose group and by 94% in the high-dose group, compared with placebo. The cumulative number of new or enlarging T2 lesions from weeks 12 to 24 was reduced by 84% in the low-dose group and by 91% in the high-dose group. The researchers observed a favorable trend toward a reduction in annualized relapse rate among treated patients, compared with controls.

The adverse event profiles were similar between groups. The most common adverse events in the treated groups, compared with placebo, were nasopharyngitis (9.4% vs 13.6%), headache (4.7% vs 9.1%), and urinary tract infection (4.7% vs 2.3%). During the first six hours after the first dose of RPC1063, maximum reductions in mean hourly heart rate were < 2 bpm from baseline, and no patient had a minimum hourly heart rate < 45 bpm. The investigators did not observe any notable cardiac, pulmonary, ophthalmologic, or malignancy adverse events.

“Both doses of RPC1063 demonstrated large, significant, and consistent reductions of all MRI measures of MS disease activity,” said Dr. Cohen. “The tolerability and safety results suggest a favorable risk–benefit profile of RPC1063 in the treatment of relapsing-remitting MS. These results support the ongoing phase III portion of the RADIANCE trial of RPC1063 vs interferon beta-1a in relapsing-remitting MS,” he concluded.

—Erik Greb

Improved Adherence to Disease-Modifying Therapy Reduces Health Care Resource Use and Medical Costs
Improved adherence to disease-modifying therapy (DMT) is associated with lower medical and indirect costs, reduced work-loss days, and decreased inpatient stays and emergency visits for patients with multiple sclerosis (MS), investigators reported.

According to published estimates, real-world adherence to DMTs in MS ranges from 41% to 88%, and higher adherence is associated with lower rates of relapse and lower costs. Sander Yermakov, from the Analysis Group in Boston, and researchers from Biogen Idec in Cambridge, Massachusetts, sought to estimate the effect of adherence to DMTs in health care resource use and cost outcomes in patients with MS and to model the impact of improving adherence on these outcomes.

A retrospective analysis was conducted using the OptumHealth Reporting & Insights employer claims database, which contains information on medical and pharmacy claims for more than 18 million beneficiaries in the US, as well as disability claims and salary information in a subset of approximately 4.2 million employees. Employed patients with two or more MS diagnoses (ICD-9-CM 340) initiating DMT from January 2, 2002, through March 31, 2012, were included in the analysis.

Direct medical costs (paid amounts to providers for services or drugs, excluding payments for DMTs), indirect costs (disability payments to employees and work-loss costs to employers), and resource use were analyzed in the six months prior to initiation of any DMT (baseline period) and for three years after initiation (follow-up period). Adherence to any DMT was defined as the proportion of days covered (PDC) and measured using the percentage of days in each follow-up period during which the patient had one or more MS DMT available.

Multivariate regression analyses were used to estimate the effect of PDC on follow-up period outcomes, controlling for baseline characteristics. The estimated model was used to predict the change in use and costs associated with a 10% improvement in PDC.

A total of 1,538 patients met the selection criteria (baseline age, 43.6; 63% female). PDC had a statistically significant effect on direct medical and indirect work productivity costs, work-loss days, and likelihood of an inpatient stay or emergency visit at one-, two-, and three-year follow-up. A 10% improvement in PDC was estimated to reduce direct costs by 4%, indirect costs by 3% to 4%, work-loss days by 3% to 7%, likelihood of an inpatient stay by 13% to 19%, and likelihood of an emergency visit by 8% to 19%, depending on the follow-up period.

The impact on the likelihood of an inpatient stay or emergency visit increased with the length of the follow-up period. In the first year, the decrease in direct costs associated with a 10% improvement in adherence was greater for patients with PDC of 0.8 or higher (10%), men (6%), and patients not on disability in the baseline period.

—Glenn S. Williams

Equivalence Demonstrated by a Generic Version of Glatiramer Acetate
Results of the randomized, double-blind GATE trial indicate that generic glatiramer acetate is equivalent to branded Copaxone in reducing the number of gadolinium-enhancing lesions, a clinically relevant end point in relapsing-remitting multiple sclerosis (RRMS). Other efficacy outcomes, safety, and tolerability also were comparable.

“This is the first generic glatiramer acetate with an efficacy and safety profile demonstrated to be equivalent to the currently marketed product,” said Jeffrey A. Cohen, MD, Director of the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, on behalf of the GATE Study Group.

“Generic alternatives to the currently approved therapies for RRMS are needed,” Dr. Cohen said. But because glatiramer acetate is a complex polypeptide mixture that precludes pharmacokinetic comparison, a generic version needs to demonstrate equivalence in efficacy and safety. The GATE trial aimed to show that generic glatiramer acetate was equivalent to Copaxone (Teva Pharmaceuticals; North Wales, Pennsylvania), as measured by MRI and clinical end points, safety, and tolerability in RRMS.

Patients with ambulatory RRMS (ages 18 to 55) with one or more relapse in the year prior to screening and one to 15 gadolinium-enhancing brain lesions were randomized in a 4.3:4.3:1 fashion in a multicenter, double-blind, placebo-controlled trial to receive 20 mg of generic glatiramer acetate, 20 mg of Copaxone, or placebo by daily subcutaneous injection for nine months. The primary end point was combined number of gadolinium-enhancing lesions over months seven, eight, and nine. Additional efficacy end points included other MRI parameters, annualized relapse rate, Expanded Disability Status Scale (EDSS) score, and freedom from disease activity. Safety and tolerability were assessed through monitoring of adverse events, injection site reactions, and routine blood laboratory tests.

A total of 794 patients were randomized and treated with generic glatiramer acetate (n = 353), Copaxone (n = 357), or placebo (n = 84). Of these, 735 patients (92.5%) completed the nine-month double-blind treatment period. The estimated geometric mean numbers of gadolinium-enhancing lesions were 0.42 for generic glatiramer acetate and 0.39 for Copaxone, resulting in an estimated generic/brand lesion ratio of 1.097 with a 95% confidence interval of 0.884 to 1.362, which is within the predefined equivalence margin.

The estimated geometric mean number of gadolinium-enhancing lesions for both the generic and brand drug groups was lower than for the placebo group, confirming assay sensitivity. Annualized relapse rates were 0.31 for generic glatiramer acetate, 0.41 for Copaxone, and 0.39 for placebo. Comparable proportions of patients treated with the generic and branded drug were free from disease activity. EDSS was stable in all three groups. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the two treatment groups.

The generic version of glatiramer acetate is being developed by Synthon Biopharmaceuticals BV (Nijmegen, the Netherlands).

—Glenn S. Williams

Does Brain Reserve Protect Against Physical Disability in MS?
Patients with multiple sclerosis (MS) who have larger maximal lifetime brain growth may have less physical disability, according to researchers. Larger maximal lifetime brain growth may help preserve patients’ ambulation and fine motor function.

“Clinical consideration of maximal lifetime brain growth … may help identify patients with MS at highest risk for future physical disability,” said James F. Sumowski, PhD, Senior Research Scientist of Neuropsychology and Neuroscience Research at the Kessler Foundation Research Center in West Orange, New Jersey. “At-risk patients can be enrolled in early intervention treatments or research on such treatments.”

Dr. Sumowski and colleagues studied 352 patients with MS, including 255 people with relapsing-remitting MS and 97 people with secondary progressive MS. The researchers assessed participants’ disease burden using high-resolution, 3-D, T1 fast field echo. They used software to normalize patients’ total brain, gray matter, white matter, deep gray matter, and thalamus volumes. The researchers also used dual-echo turbo spin echo to quantify T2 lesion volume. Dr. Sumowski’s group estimated maximal lifetime brain growth with SIENAX v-scaling factor (adjusted for gender), a proxy for intracranial volume.

In addition, the investigators assessed 168 participants’ ambulation with the 25-Foot Walk. Participants who used assistive devices for walking were excluded. Fine motor function was assessed with the Nine-Hole Peg Test (in 323 patients) and Finger Tapping Test (in 330 patients). Cognitive status was assessed in 333 patients with the Paced Auditory Serial Addition Test-3 (PASAT-3).

Dr. Sumowski and colleagues found that maximal lifetime brain growth significantly predicted pyramidal and cerebellar function. Maximal lifetime brain growth accounted for the variance between patients in physical disability, as measured by the Finger Tapping Test. People with larger maximal lifetime brain growth performed better on that test. Disability was worse in people with smaller maximal lifetime brain growth, and the relationship did not change when the researchers controlled for demographics and deep gray matter atrophy.

The investigators found a similar relationship for cerebellar function. Participants with larger maximal lifetime brain growth had less disability and cerebellar dysfunction, even when the researchers controlled for demographics and disease burden. Patients with larger maximal lifetime brain growth completed the 25-Foot Walk more quickly, which indicated that they had less disability.

The researchers did not find a relationship between maximal lifetime brain growth and other functional systems, such as brainstem, visual, motor sensory, and bladder function.

—Erik Greb

BOSTON—More than 45 new multiple sclerosis (MS) susceptibility variants were reported by researchers.

“We now present a comprehensive view of MS genetic susceptibility and provide a detailed map of proximal biologic effects that identify new molecular pathways involved in the transition from health to MS,” said Philip Laurence De Jager, MD, PhD, Assistant Professor, Harvard Medical School in Boston, on behalf of the International MS Genetics Consortium.

To identify MS susceptibility associations outside the validated MS susceptibility loci and uncover new biologic processes that drive the onset of MS, the researchers conducted a genomewide discovery study of approximately eight million single-nucleotide polymorphisms (SNPs) in each of 14,802 MS cases and 26,703 controls. This step was followed by a deep replication study of more than 80,000 SNPs in more than 19,217 MS cases and 17,842 controls. The 4,716 SNPs with a P value of less than 0.05 in the discovery study were included in the present study. Functional evaluations of the results were conducted using DEPICT for pathway analysis, as well as analyses of immune cell RNA expression data from ImmVar and reference epigenomic maps from the Epigenome Roadmap and ENCODE projects.

At the end of the replication study, more than 45 new susceptibility variants were identified, with 10 major histocompatibility complex (MHC) and more than 150 non-MHC SNPs meeting a threshold of genomewide significance. The depth of the replication effort identified multiple independent effects in many regions that were previously unresolvable. For example, the EVI5 region has as many as four independent susceptibility variants.

“Uncovering this multiplicity of associations in certain regions is critical to our efforts to model the biologic consequences of MS susceptibility variants and to develop predictive algorithms,” Dr. De Jager said. “With more than 150 independent susceptibility effects and a high resolution analysis of each locus in hand, we have created a reference map of MS susceptibility and now turn to the task of understanding the biology of MS susceptibility.

“With the new MS map and multiple approaches to epigenomic annotation and functional evaluations, it is clear that non-TH1/Th17/Treg processes are important in the onset of MS,” he continued. “Myeloid, NK, and CD8 cells are now implicated, and B and dendritic cell functions are suggested to be altered by MS variants.”

Leveraging RNA data from 405 subjects with purified CD4 T and monocytes, 29% of MS variants with RNA effects are unique to monocytes, which is now the same proportion as for T cells (29%). Pathway analyses highlighted an enrichment of NK and B cell activation molecular networks in addition to T cell effects.

—Glenn S. Williams

Investigational Oral Drug Reduces Disease Activity in Relapsing-Remitting MS
An oral, selective sphingosine 1-phosphate 1 receptor modulator appears to reduce MRI measures of disease activity in patients with relapsing-remitting multiple sclerosis (MS), according to data presented. The drug, RPC1063, may be safe and tolerable for these patients.

Data are from the international, combined phase II/III RADIANCE trial. Jeffrey Cohen, MD, Director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research in Cleveland, and colleagues randomized 258 patients with relapsing-remitting MS. A total of 87 participants received a low dose (0.5 mg) of RPC1063, 83 participants received a high dose (1.0 mg) of RPC1063, and 88 participants received placebo for 24 weeks.

The trial’s primary end point was the cumulative number of total gadolinium-enhancing lesions on MRI at weeks 12, 16, 20, and 24. Key secondary end points included the number of gadolinium-enhancing lesions at week 24, the cumulative number of new or enlarging T2 lesions from weeks 12 to 24, and annualized relapse rate.

The researchers assessed safety using vital signs, laboratory tests, ECG, Holter monitoring, pulmonary function test, optical coherence tomography, and adverse events. Patients were titrated to their assigned doses during one week to mitigate the first doses’ effects on heart rate.

Approximately 98% of patients completed the trial. The cumulative number of gadolinium-enhancing lesions from weeks 12 to 24 was reduced by 86% in both treatment arms, compared with placebo. The numbers of gadolinium-enhancing lesions at week 24 were significantly reduced by 91% in the low-dose group and by 94% in the high-dose group, compared with placebo. The cumulative number of new or enlarging T2 lesions from weeks 12 to 24 was reduced by 84% in the low-dose group and by 91% in the high-dose group. The researchers observed a favorable trend toward a reduction in annualized relapse rate among treated patients, compared with controls.

The adverse event profiles were similar between groups. The most common adverse events in the treated groups, compared with placebo, were nasopharyngitis (9.4% vs 13.6%), headache (4.7% vs 9.1%), and urinary tract infection (4.7% vs 2.3%). During the first six hours after the first dose of RPC1063, maximum reductions in mean hourly heart rate were < 2 bpm from baseline, and no patient had a minimum hourly heart rate < 45 bpm. The investigators did not observe any notable cardiac, pulmonary, ophthalmologic, or malignancy adverse events.

“Both doses of RPC1063 demonstrated large, significant, and consistent reductions of all MRI measures of MS disease activity,” said Dr. Cohen. “The tolerability and safety results suggest a favorable risk–benefit profile of RPC1063 in the treatment of relapsing-remitting MS. These results support the ongoing phase III portion of the RADIANCE trial of RPC1063 vs interferon beta-1a in relapsing-remitting MS,” he concluded.

—Erik Greb

Improved Adherence to Disease-Modifying Therapy Reduces Health Care Resource Use and Medical Costs
Improved adherence to disease-modifying therapy (DMT) is associated with lower medical and indirect costs, reduced work-loss days, and decreased inpatient stays and emergency visits for patients with multiple sclerosis (MS), investigators reported.

According to published estimates, real-world adherence to DMTs in MS ranges from 41% to 88%, and higher adherence is associated with lower rates of relapse and lower costs. Sander Yermakov, from the Analysis Group in Boston, and researchers from Biogen Idec in Cambridge, Massachusetts, sought to estimate the effect of adherence to DMTs in health care resource use and cost outcomes in patients with MS and to model the impact of improving adherence on these outcomes.

A retrospective analysis was conducted using the OptumHealth Reporting & Insights employer claims database, which contains information on medical and pharmacy claims for more than 18 million beneficiaries in the US, as well as disability claims and salary information in a subset of approximately 4.2 million employees. Employed patients with two or more MS diagnoses (ICD-9-CM 340) initiating DMT from January 2, 2002, through March 31, 2012, were included in the analysis.

Direct medical costs (paid amounts to providers for services or drugs, excluding payments for DMTs), indirect costs (disability payments to employees and work-loss costs to employers), and resource use were analyzed in the six months prior to initiation of any DMT (baseline period) and for three years after initiation (follow-up period). Adherence to any DMT was defined as the proportion of days covered (PDC) and measured using the percentage of days in each follow-up period during which the patient had one or more MS DMT available.

Multivariate regression analyses were used to estimate the effect of PDC on follow-up period outcomes, controlling for baseline characteristics. The estimated model was used to predict the change in use and costs associated with a 10% improvement in PDC.

A total of 1,538 patients met the selection criteria (baseline age, 43.6; 63% female). PDC had a statistically significant effect on direct medical and indirect work productivity costs, work-loss days, and likelihood of an inpatient stay or emergency visit at one-, two-, and three-year follow-up. A 10% improvement in PDC was estimated to reduce direct costs by 4%, indirect costs by 3% to 4%, work-loss days by 3% to 7%, likelihood of an inpatient stay by 13% to 19%, and likelihood of an emergency visit by 8% to 19%, depending on the follow-up period.

The impact on the likelihood of an inpatient stay or emergency visit increased with the length of the follow-up period. In the first year, the decrease in direct costs associated with a 10% improvement in adherence was greater for patients with PDC of 0.8 or higher (10%), men (6%), and patients not on disability in the baseline period.

—Glenn S. Williams

Equivalence Demonstrated by a Generic Version of Glatiramer Acetate
Results of the randomized, double-blind GATE trial indicate that generic glatiramer acetate is equivalent to branded Copaxone in reducing the number of gadolinium-enhancing lesions, a clinically relevant end point in relapsing-remitting multiple sclerosis (RRMS). Other efficacy outcomes, safety, and tolerability also were comparable.

“This is the first generic glatiramer acetate with an efficacy and safety profile demonstrated to be equivalent to the currently marketed product,” said Jeffrey A. Cohen, MD, Director of the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, on behalf of the GATE Study Group.

“Generic alternatives to the currently approved therapies for RRMS are needed,” Dr. Cohen said. But because glatiramer acetate is a complex polypeptide mixture that precludes pharmacokinetic comparison, a generic version needs to demonstrate equivalence in efficacy and safety. The GATE trial aimed to show that generic glatiramer acetate was equivalent to Copaxone (Teva Pharmaceuticals; North Wales, Pennsylvania), as measured by MRI and clinical end points, safety, and tolerability in RRMS.

Patients with ambulatory RRMS (ages 18 to 55) with one or more relapse in the year prior to screening and one to 15 gadolinium-enhancing brain lesions were randomized in a 4.3:4.3:1 fashion in a multicenter, double-blind, placebo-controlled trial to receive 20 mg of generic glatiramer acetate, 20 mg of Copaxone, or placebo by daily subcutaneous injection for nine months. The primary end point was combined number of gadolinium-enhancing lesions over months seven, eight, and nine. Additional efficacy end points included other MRI parameters, annualized relapse rate, Expanded Disability Status Scale (EDSS) score, and freedom from disease activity. Safety and tolerability were assessed through monitoring of adverse events, injection site reactions, and routine blood laboratory tests.

A total of 794 patients were randomized and treated with generic glatiramer acetate (n = 353), Copaxone (n = 357), or placebo (n = 84). Of these, 735 patients (92.5%) completed the nine-month double-blind treatment period. The estimated geometric mean numbers of gadolinium-enhancing lesions were 0.42 for generic glatiramer acetate and 0.39 for Copaxone, resulting in an estimated generic/brand lesion ratio of 1.097 with a 95% confidence interval of 0.884 to 1.362, which is within the predefined equivalence margin.

The estimated geometric mean number of gadolinium-enhancing lesions for both the generic and brand drug groups was lower than for the placebo group, confirming assay sensitivity. Annualized relapse rates were 0.31 for generic glatiramer acetate, 0.41 for Copaxone, and 0.39 for placebo. Comparable proportions of patients treated with the generic and branded drug were free from disease activity. EDSS was stable in all three groups. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the two treatment groups.

The generic version of glatiramer acetate is being developed by Synthon Biopharmaceuticals BV (Nijmegen, the Netherlands).

—Glenn S. Williams

Does Brain Reserve Protect Against Physical Disability in MS?
Patients with multiple sclerosis (MS) who have larger maximal lifetime brain growth may have less physical disability, according to researchers. Larger maximal lifetime brain growth may help preserve patients’ ambulation and fine motor function.

“Clinical consideration of maximal lifetime brain growth … may help identify patients with MS at highest risk for future physical disability,” said James F. Sumowski, PhD, Senior Research Scientist of Neuropsychology and Neuroscience Research at the Kessler Foundation Research Center in West Orange, New Jersey. “At-risk patients can be enrolled in early intervention treatments or research on such treatments.”

Dr. Sumowski and colleagues studied 352 patients with MS, including 255 people with relapsing-remitting MS and 97 people with secondary progressive MS. The researchers assessed participants’ disease burden using high-resolution, 3-D, T1 fast field echo. They used software to normalize patients’ total brain, gray matter, white matter, deep gray matter, and thalamus volumes. The researchers also used dual-echo turbo spin echo to quantify T2 lesion volume. Dr. Sumowski’s group estimated maximal lifetime brain growth with SIENAX v-scaling factor (adjusted for gender), a proxy for intracranial volume.

In addition, the investigators assessed 168 participants’ ambulation with the 25-Foot Walk. Participants who used assistive devices for walking were excluded. Fine motor function was assessed with the Nine-Hole Peg Test (in 323 patients) and Finger Tapping Test (in 330 patients). Cognitive status was assessed in 333 patients with the Paced Auditory Serial Addition Test-3 (PASAT-3).

Dr. Sumowski and colleagues found that maximal lifetime brain growth significantly predicted pyramidal and cerebellar function. Maximal lifetime brain growth accounted for the variance between patients in physical disability, as measured by the Finger Tapping Test. People with larger maximal lifetime brain growth performed better on that test. Disability was worse in people with smaller maximal lifetime brain growth, and the relationship did not change when the researchers controlled for demographics and deep gray matter atrophy.

The investigators found a similar relationship for cerebellar function. Participants with larger maximal lifetime brain growth had less disability and cerebellar dysfunction, even when the researchers controlled for demographics and disease burden. Patients with larger maximal lifetime brain growth completed the 25-Foot Walk more quickly, which indicated that they had less disability.

The researchers did not find a relationship between maximal lifetime brain growth and other functional systems, such as brainstem, visual, motor sensory, and bladder function.

—Erik Greb

PHILADELPHIA—A computerized tool is a valid means of performing cognitive testing for patients with multiple sclerosis (MS), according to research presented at the 66th Annual Meeting of the American Academy of Neurology.

NeuroTrax provides a global cognitive score along with scores for individual cognitive domains. Results of NeuroTrax assessments correlate well with results of the Symbol Digit Modalities Test (SDMT), which provides a single, global score “and does not allow us to appreciate the richness and variability of domains of cognition that can be impaired differentially,” according to Mark Gudesblatt, MD.

“Easily utilized objective cognitive screens are needed to evaluate the cognitive impact of MS independent of Expanded Disability Status Scale score or MRI,” said Dr. Gudesblatt, a neurologist at South Shore Neurologic Associates in Patchogue, New York. “Additional studies of cognitive screening tools and correlation to previously utilized clinical trial measures are necessary to facilitate widespread acceptance and incorporation of these tools into routine MS care and patient management.”

Dr. Gudesblatt and his colleagues conducted a retrospective review of data for 113 consecutive patients with MS who were referred for cognitive testing during the course of routine clinical care. The patients were evaluated with the oral version of SDMT and NeuroTrax testing on the same day. The researchers used Centofanti (1975) age norms to standardize the SDMT raw scores. Patients’ ages ranged between approximately 20 and 83, and the population’s mean age was approximately 49. About 85% of participants were female. Patients had an average of about 15 years of education.

The patients’ standardized SDMT scores significantly correlated with NeuroTrax global cognitive scores. Standardized SDMT scores also significantly correlated with NeuroTrax scores on seven individual cognitive domain indices, including executive function, memory, attention, visual spatial processing, information processing speed, motor skill, and verbal function. The three individual cognitive domain scores on NeuroTrax that most strongly correlated with SDMT scores were executive function, memory, and attention.

In addition, SDMT score was correlated with the number of NeuroTrax index scores greater than 1 SD below average for norms of cognitive health, age, and education. The researchers classified SDMT subgroups, according to the SDMT manual, as less than 1 SD below average, less than 1.5 SD below average (low), less than 2 SD below average (moderately low), and 2 or more SD below average (very low). Mean NeuroTrax global cognitive scores for these subgroups were 99.1, 93.0, 83.9, and 76.9, respectively. The researchers observed a similar pattern for all NeuroTrax domain index scores, especially executive function and attention. Neurotrax’s ability to identify individual domains of impairment and categorize the number of domains that were impaired “improves our ability to identify and appreciate the variable impact and burden of neurologic diseases like MS,” said Dr. Gudesblatt.

This retrospective review supports the construct validity of the NeuroTrax cognitive assessment tool, said Dr. Gudesblatt. “Routine use of cognitive screening in the care of patients with MS is not as common as is likely warranted,” he added. “Computerized cognitive testing may provide an easy, independent, objective screening tool that taps into broader sets of cognitive domains.”

—Erik Greb

PHILADELPHIA—A computerized tool is a valid means of performing cognitive testing for patients with multiple sclerosis (MS), according to research presented at the 66th Annual Meeting of the American Academy of Neurology.

NeuroTrax provides a global cognitive score along with scores for individual cognitive domains. Results of NeuroTrax assessments correlate well with results of the Symbol Digit Modalities Test (SDMT), which provides a single, global score “and does not allow us to appreciate the richness and variability of domains of cognition that can be impaired differentially,” according to Mark Gudesblatt, MD.

“Easily utilized objective cognitive screens are needed to evaluate the cognitive impact of MS independent of Expanded Disability Status Scale score or MRI,” said Dr. Gudesblatt, a neurologist at South Shore Neurologic Associates in Patchogue, New York. “Additional studies of cognitive screening tools and correlation to previously utilized clinical trial measures are necessary to facilitate widespread acceptance and incorporation of these tools into routine MS care and patient management.”

Dr. Gudesblatt and his colleagues conducted a retrospective review of data for 113 consecutive patients with MS who were referred for cognitive testing during the course of routine clinical care. The patients were evaluated with the oral version of SDMT and NeuroTrax testing on the same day. The researchers used Centofanti (1975) age norms to standardize the SDMT raw scores. Patients’ ages ranged between approximately 20 and 83, and the population’s mean age was approximately 49. About 85% of participants were female. Patients had an average of about 15 years of education.

The patients’ standardized SDMT scores significantly correlated with NeuroTrax global cognitive scores. Standardized SDMT scores also significantly correlated with NeuroTrax scores on seven individual cognitive domain indices, including executive function, memory, attention, visual spatial processing, information processing speed, motor skill, and verbal function. The three individual cognitive domain scores on NeuroTrax that most strongly correlated with SDMT scores were executive function, memory, and attention.

In addition, SDMT score was correlated with the number of NeuroTrax index scores greater than 1 SD below average for norms of cognitive health, age, and education. The researchers classified SDMT subgroups, according to the SDMT manual, as less than 1 SD below average, less than 1.5 SD below average (low), less than 2 SD below average (moderately low), and 2 or more SD below average (very low). Mean NeuroTrax global cognitive scores for these subgroups were 99.1, 93.0, 83.9, and 76.9, respectively. The researchers observed a similar pattern for all NeuroTrax domain index scores, especially executive function and attention. Neurotrax’s ability to identify individual domains of impairment and categorize the number of domains that were impaired “improves our ability to identify and appreciate the variable impact and burden of neurologic diseases like MS,” said Dr. Gudesblatt.

This retrospective review supports the construct validity of the NeuroTrax cognitive assessment tool, said Dr. Gudesblatt. “Routine use of cognitive screening in the care of patients with MS is not as common as is likely warranted,” he added. “Computerized cognitive testing may provide an easy, independent, objective screening tool that taps into broader sets of cognitive domains.”

—Erik Greb

PHILADELPHIA—A computerized tool is a valid means of performing cognitive testing for patients with multiple sclerosis (MS), according to research presented at the 66th Annual Meeting of the American Academy of Neurology.

NeuroTrax provides a global cognitive score along with scores for individual cognitive domains. Results of NeuroTrax assessments correlate well with results of the Symbol Digit Modalities Test (SDMT), which provides a single, global score “and does not allow us to appreciate the richness and variability of domains of cognition that can be impaired differentially,” according to Mark Gudesblatt, MD.

“Easily utilized objective cognitive screens are needed to evaluate the cognitive impact of MS independent of Expanded Disability Status Scale score or MRI,” said Dr. Gudesblatt, a neurologist at South Shore Neurologic Associates in Patchogue, New York. “Additional studies of cognitive screening tools and correlation to previously utilized clinical trial measures are necessary to facilitate widespread acceptance and incorporation of these tools into routine MS care and patient management.”

Dr. Gudesblatt and his colleagues conducted a retrospective review of data for 113 consecutive patients with MS who were referred for cognitive testing during the course of routine clinical care. The patients were evaluated with the oral version of SDMT and NeuroTrax testing on the same day. The researchers used Centofanti (1975) age norms to standardize the SDMT raw scores. Patients’ ages ranged between approximately 20 and 83, and the population’s mean age was approximately 49. About 85% of participants were female. Patients had an average of about 15 years of education.

The patients’ standardized SDMT scores significantly correlated with NeuroTrax global cognitive scores. Standardized SDMT scores also significantly correlated with NeuroTrax scores on seven individual cognitive domain indices, including executive function, memory, attention, visual spatial processing, information processing speed, motor skill, and verbal function. The three individual cognitive domain scores on NeuroTrax that most strongly correlated with SDMT scores were executive function, memory, and attention.

In addition, SDMT score was correlated with the number of NeuroTrax index scores greater than 1 SD below average for norms of cognitive health, age, and education. The researchers classified SDMT subgroups, according to the SDMT manual, as less than 1 SD below average, less than 1.5 SD below average (low), less than 2 SD below average (moderately low), and 2 or more SD below average (very low). Mean NeuroTrax global cognitive scores for these subgroups were 99.1, 93.0, 83.9, and 76.9, respectively. The researchers observed a similar pattern for all NeuroTrax domain index scores, especially executive function and attention. Neurotrax’s ability to identify individual domains of impairment and categorize the number of domains that were impaired “improves our ability to identify and appreciate the variable impact and burden of neurologic diseases like MS,” said Dr. Gudesblatt.

This retrospective review supports the construct validity of the NeuroTrax cognitive assessment tool, said Dr. Gudesblatt. “Routine use of cognitive screening in the care of patients with MS is not as common as is likely warranted,” he added. “Computerized cognitive testing may provide an easy, independent, objective screening tool that taps into broader sets of cognitive domains.”

—Erik Greb