ICYMI Multiple Sclerosis

ORLANDO—For patients with relapsing-remitting multiple sclerosis (MS), MRI activity unaccompanied by any other clinical event may be the strongest predictor of switching from a first-line disease-modifying therapy (DMT), according to research presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. Individuals with MRI worsening alone may be 6.3 times as likely to switch DMTs than patients with one relapse.

In addition, worsening on the Expanded Disability Status Scale (EDSS) alone or EDSS and MRI worsening nearly tripled the odds of switching DMTs, compared with having one relapse, said Barbara Teter, PhD, Director of Research and Development at the New York State MS Consortium in Buffalo. Patients with two or more relapses as a first event following DMT initiation were 2.8 times as likely to switch DMTs, compared with patients with a single relapse.

A Retrospective Analysis of Longitudinal Registry Data
To identify clinical and demographic characteristics that predict switching to a new DMT among patients with relapsing-remitting MS, Dr. Teter and her colleagues conducted a retrospective study of longitudinal registry data from 14 MS Centers or neurology practices in the state of New York. The researchers analyzed data for patients enrolled in the registry from 1996 to 2009, and nine MS treatment centers participated in chart review follow-up.

Eligible study participants had three or more years of follow-up and used interferon beta or glatiramer acetate as an initial DMT. Suboptimal response to the first DMT was defined as a relapse, EDSS worsening, MRI worsening (eg, new gadolinium-enhancing or T2 lesions), or a combination of these events. Patients who discontinued their initial DMT and started another DMT within six to 12 months after the first MS event were considered to have switched therapies. The investigators used regression modeling to identify predictors of DMT switching.

Patients Who Switched DMTs Were More Likely to Be Younger
Patients who switched therapies were more likely to be younger at symptom onset and younger at DMT initiation than patients who did not switch. Among patients with MRI worsening alone, the mean time between DMT initiation and first MS event was longer among patients who switched DMTs (62.3 months) than among patients who did not switch (38.5 months).

Patients were less likely to switch therapies if they experienced combinations of one relapse plus EDSS worsening and one relapse plus EDSS worsening plus MRI worsening than if they had one relapse alone, said Dr. Teter. Combinations of two or more relapses plus EDSS worsening or MRI worsening did not predict a DMT switch, but the sample size was small.

“The likelihood and drivers of therapy switch may change with expanding therapy options,” said Dr. Teter. “At the time of this study, few therapy options were available.”

—Erik Greb
Senior Associate Editor

ORLANDO—For patients with relapsing-remitting multiple sclerosis (MS), MRI activity unaccompanied by any other clinical event may be the strongest predictor of switching from a first-line disease-modifying therapy (DMT), according to research presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. Individuals with MRI worsening alone may be 6.3 times as likely to switch DMTs than patients with one relapse.

In addition, worsening on the Expanded Disability Status Scale (EDSS) alone or EDSS and MRI worsening nearly tripled the odds of switching DMTs, compared with having one relapse, said Barbara Teter, PhD, Director of Research and Development at the New York State MS Consortium in Buffalo. Patients with two or more relapses as a first event following DMT initiation were 2.8 times as likely to switch DMTs, compared with patients with a single relapse.

A Retrospective Analysis of Longitudinal Registry Data
To identify clinical and demographic characteristics that predict switching to a new DMT among patients with relapsing-remitting MS, Dr. Teter and her colleagues conducted a retrospective study of longitudinal registry data from 14 MS Centers or neurology practices in the state of New York. The researchers analyzed data for patients enrolled in the registry from 1996 to 2009, and nine MS treatment centers participated in chart review follow-up.

Eligible study participants had three or more years of follow-up and used interferon beta or glatiramer acetate as an initial DMT. Suboptimal response to the first DMT was defined as a relapse, EDSS worsening, MRI worsening (eg, new gadolinium-enhancing or T2 lesions), or a combination of these events. Patients who discontinued their initial DMT and started another DMT within six to 12 months after the first MS event were considered to have switched therapies. The investigators used regression modeling to identify predictors of DMT switching.

Patients Who Switched DMTs Were More Likely to Be Younger
Patients who switched therapies were more likely to be younger at symptom onset and younger at DMT initiation than patients who did not switch. Among patients with MRI worsening alone, the mean time between DMT initiation and first MS event was longer among patients who switched DMTs (62.3 months) than among patients who did not switch (38.5 months).

Patients were less likely to switch therapies if they experienced combinations of one relapse plus EDSS worsening and one relapse plus EDSS worsening plus MRI worsening than if they had one relapse alone, said Dr. Teter. Combinations of two or more relapses plus EDSS worsening or MRI worsening did not predict a DMT switch, but the sample size was small.

“The likelihood and drivers of therapy switch may change with expanding therapy options,” said Dr. Teter. “At the time of this study, few therapy options were available.”

—Erik Greb
Senior Associate Editor

ORLANDO—For patients with relapsing-remitting multiple sclerosis (MS), MRI activity unaccompanied by any other clinical event may be the strongest predictor of switching from a first-line disease-modifying therapy (DMT), according to research presented at the Fifth Cooperative Meeting of the Consortium of MS Centers and the Americas Committee for Treatment and Research in MS. Individuals with MRI worsening alone may be 6.3 times as likely to switch DMTs than patients with one relapse.

In addition, worsening on the Expanded Disability Status Scale (EDSS) alone or EDSS and MRI worsening nearly tripled the odds of switching DMTs, compared with having one relapse, said Barbara Teter, PhD, Director of Research and Development at the New York State MS Consortium in Buffalo. Patients with two or more relapses as a first event following DMT initiation were 2.8 times as likely to switch DMTs, compared with patients with a single relapse.

A Retrospective Analysis of Longitudinal Registry Data
To identify clinical and demographic characteristics that predict switching to a new DMT among patients with relapsing-remitting MS, Dr. Teter and her colleagues conducted a retrospective study of longitudinal registry data from 14 MS Centers or neurology practices in the state of New York. The researchers analyzed data for patients enrolled in the registry from 1996 to 2009, and nine MS treatment centers participated in chart review follow-up.

Eligible study participants had three or more years of follow-up and used interferon beta or glatiramer acetate as an initial DMT. Suboptimal response to the first DMT was defined as a relapse, EDSS worsening, MRI worsening (eg, new gadolinium-enhancing or T2 lesions), or a combination of these events. Patients who discontinued their initial DMT and started another DMT within six to 12 months after the first MS event were considered to have switched therapies. The investigators used regression modeling to identify predictors of DMT switching.

Patients Who Switched DMTs Were More Likely to Be Younger
Patients who switched therapies were more likely to be younger at symptom onset and younger at DMT initiation than patients who did not switch. Among patients with MRI worsening alone, the mean time between DMT initiation and first MS event was longer among patients who switched DMTs (62.3 months) than among patients who did not switch (38.5 months).

Patients were less likely to switch therapies if they experienced combinations of one relapse plus EDSS worsening and one relapse plus EDSS worsening plus MRI worsening than if they had one relapse alone, said Dr. Teter. Combinations of two or more relapses plus EDSS worsening or MRI worsening did not predict a DMT switch, but the sample size was small.

“The likelihood and drivers of therapy switch may change with expanding therapy options,” said Dr. Teter. “At the time of this study, few therapy options were available.”

—Erik Greb
Senior Associate Editor

COPENHAGEN—Dysfunction within the pyramidal system may be the strongest independent clinical predictor of disability progression in patients with clinically isolated syndrome (CIS), according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Older age at CIS onset, however, may be a poor prognostic indicator. Factors that predict disability progression in patients with relapsing-remitting MS may also predict the same outcome in patients with CIS.

Natural history studies indicate that high T2 lesion burden is a poor prognostic indicator, but “in our study, this [finding] is confounded by treatment,” said Vilija Jokubaitis, PhD, researcher in the Department of Medicine at the University of Melbourne. Dr. Jokubaitis and colleagues found that high T2 lesion load was associated with earlier and longer treatment exposure.

The researchers also observed that exposure to disease-modifying therapies (DMTs) significantly delayed the accumulation of disability. The investigators found an association between increase in treatment exposure and a decrease in the hazard of progression. “Our data suggest that the early and consistent use of DMTs is key in delaying the accumulation of MS-related disability,” said Dr. Jokubaitis.

Monitoring for Disability Progression
Dr. Jokubaitis and colleagues analyzed data from the MSBase Incidence Study, an investigator-initiated, prospective, observational cohort study of patients with CIS. The study began collecting data in 17 countries in 2004. Persons who had been diagnosed with CIS within 12 months of onset were enrolled into this study.

At baseline, the researchers collected demographic information, Expanded Disability Status Scale (EDSS) scores, Kurtzke functional scores (KFS), and cerebral MRI. Baseline MRI scans were available for 89% of the patients. At follow-up, the investigators collected EDSS scores, KFS, relapse information, and information about changes in treatments. The study’s primary end point was disability progression events, which were defined as an EDSS score increase of at least one point above a minimum baseline EDSS score of 1. The increase had to be maintained for a particular period of time. The study focused on disability progression events at three months and at 12 months.

A total of 1,989 patients had at least three EDSS scores spanning a minimum of nine months. Of these patients, 391 had a three-month confirmed disability progression event, and the event was maintained for at least 12 months in 307 patients.

First-Line Drugs Had Equivalent Efficacy
Approximately 71% of patients were female. Patients’ average age at CIS onset was 33, and their median EDSS score at baseline was 1.5. About 9% of patients had fewer than three T2 lesions on cerebral MRI.

Hazard regression analysis indicated that every 10 years of age were associated with a 1.17 increase in the hazard of disease progression. A KFS of 2 or greater was associated with roughly a 1.5-fold increase in the risk of disability progression, compared with patients who had a pyramidal KFS of 0 or 1.

To assess the effect of treatment, the researchers compared patients who were treated before the accumulation of disability with patients who were untreated before the accumulation of disability. All first-line injectable drugs decreased patients’ risk of progression by approximately 50%.

—Erik Greb
Senior Associate Editor

COPENHAGEN—Dysfunction within the pyramidal system may be the strongest independent clinical predictor of disability progression in patients with clinically isolated syndrome (CIS), according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Older age at CIS onset, however, may be a poor prognostic indicator. Factors that predict disability progression in patients with relapsing-remitting MS may also predict the same outcome in patients with CIS.

Natural history studies indicate that high T2 lesion burden is a poor prognostic indicator, but “in our study, this [finding] is confounded by treatment,” said Vilija Jokubaitis, PhD, researcher in the Department of Medicine at the University of Melbourne. Dr. Jokubaitis and colleagues found that high T2 lesion load was associated with earlier and longer treatment exposure.

The researchers also observed that exposure to disease-modifying therapies (DMTs) significantly delayed the accumulation of disability. The investigators found an association between increase in treatment exposure and a decrease in the hazard of progression. “Our data suggest that the early and consistent use of DMTs is key in delaying the accumulation of MS-related disability,” said Dr. Jokubaitis.

Monitoring for Disability Progression
Dr. Jokubaitis and colleagues analyzed data from the MSBase Incidence Study, an investigator-initiated, prospective, observational cohort study of patients with CIS. The study began collecting data in 17 countries in 2004. Persons who had been diagnosed with CIS within 12 months of onset were enrolled into this study.

At baseline, the researchers collected demographic information, Expanded Disability Status Scale (EDSS) scores, Kurtzke functional scores (KFS), and cerebral MRI. Baseline MRI scans were available for 89% of the patients. At follow-up, the investigators collected EDSS scores, KFS, relapse information, and information about changes in treatments. The study’s primary end point was disability progression events, which were defined as an EDSS score increase of at least one point above a minimum baseline EDSS score of 1. The increase had to be maintained for a particular period of time. The study focused on disability progression events at three months and at 12 months.

A total of 1,989 patients had at least three EDSS scores spanning a minimum of nine months. Of these patients, 391 had a three-month confirmed disability progression event, and the event was maintained for at least 12 months in 307 patients.

First-Line Drugs Had Equivalent Efficacy
Approximately 71% of patients were female. Patients’ average age at CIS onset was 33, and their median EDSS score at baseline was 1.5. About 9% of patients had fewer than three T2 lesions on cerebral MRI.

Hazard regression analysis indicated that every 10 years of age were associated with a 1.17 increase in the hazard of disease progression. A KFS of 2 or greater was associated with roughly a 1.5-fold increase in the risk of disability progression, compared with patients who had a pyramidal KFS of 0 or 1.

To assess the effect of treatment, the researchers compared patients who were treated before the accumulation of disability with patients who were untreated before the accumulation of disability. All first-line injectable drugs decreased patients’ risk of progression by approximately 50%.

—Erik Greb
Senior Associate Editor

COPENHAGEN—Dysfunction within the pyramidal system may be the strongest independent clinical predictor of disability progression in patients with clinically isolated syndrome (CIS), according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Older age at CIS onset, however, may be a poor prognostic indicator. Factors that predict disability progression in patients with relapsing-remitting MS may also predict the same outcome in patients with CIS.

Natural history studies indicate that high T2 lesion burden is a poor prognostic indicator, but “in our study, this [finding] is confounded by treatment,” said Vilija Jokubaitis, PhD, researcher in the Department of Medicine at the University of Melbourne. Dr. Jokubaitis and colleagues found that high T2 lesion load was associated with earlier and longer treatment exposure.

The researchers also observed that exposure to disease-modifying therapies (DMTs) significantly delayed the accumulation of disability. The investigators found an association between increase in treatment exposure and a decrease in the hazard of progression. “Our data suggest that the early and consistent use of DMTs is key in delaying the accumulation of MS-related disability,” said Dr. Jokubaitis.

Monitoring for Disability Progression
Dr. Jokubaitis and colleagues analyzed data from the MSBase Incidence Study, an investigator-initiated, prospective, observational cohort study of patients with CIS. The study began collecting data in 17 countries in 2004. Persons who had been diagnosed with CIS within 12 months of onset were enrolled into this study.

At baseline, the researchers collected demographic information, Expanded Disability Status Scale (EDSS) scores, Kurtzke functional scores (KFS), and cerebral MRI. Baseline MRI scans were available for 89% of the patients. At follow-up, the investigators collected EDSS scores, KFS, relapse information, and information about changes in treatments. The study’s primary end point was disability progression events, which were defined as an EDSS score increase of at least one point above a minimum baseline EDSS score of 1. The increase had to be maintained for a particular period of time. The study focused on disability progression events at three months and at 12 months.

A total of 1,989 patients had at least three EDSS scores spanning a minimum of nine months. Of these patients, 391 had a three-month confirmed disability progression event, and the event was maintained for at least 12 months in 307 patients.

First-Line Drugs Had Equivalent Efficacy
Approximately 71% of patients were female. Patients’ average age at CIS onset was 33, and their median EDSS score at baseline was 1.5. About 9% of patients had fewer than three T2 lesions on cerebral MRI.

Hazard regression analysis indicated that every 10 years of age were associated with a 1.17 increase in the hazard of disease progression. A KFS of 2 or greater was associated with roughly a 1.5-fold increase in the risk of disability progression, compared with patients who had a pyramidal KFS of 0 or 1.

To assess the effect of treatment, the researchers compared patients who were treated before the accumulation of disability with patients who were untreated before the accumulation of disability. All first-line injectable drugs decreased patients’ risk of progression by approximately 50%.

—Erik Greb
Senior Associate Editor

COPENHAGEN—Serum vitamin D level early in the course of multiple sclerosis (MS) may predict a patient’s rate of long-term progression, according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Vitamin D level appears to have an inverse correlation with the number of relapses, the amount of MRI activity, the number of new active lesions, and the amount of brain atrophy over five years.

The study results suggest that vitamin D supplementation may have a role in the early treatment of MS, particularly for patients who have vitamin D insufficiency or deficiency, said Alberto Ascherio, MD, Professor of Epidemiology and Nutrition at the Harvard School of Public Health in Boston. For the purposes of the study, a serum vitamin D level of 50 nmol/L or higher was considered sufficient.

The BENEFIT Trial
To determine whether serum vitamin D levels predict disease activity after clinically isolated syndrome (CIS), Dr. Ascherio and colleagues examined data from the BENEFIT study, a randomized trial that compared the effects of early and delayed treatment with interferon beta-1b in patients with CIS. A total of 468 patients were randomized. The BENEFIT investigators measured participants’ serum 25(OH)D concentrations at baseline, six months, 12 months, and 24 months and performed clinical and MRI assessments at established intervals. At 24 months, patients entered the trial’s open phase and were offered treatment with interferon beta. Clinical and MRI follow-up lasted for five years.

Dr. Ascherio and colleagues created Cox proportional hazard models or generalized mixed effects models to analyze the data. They adjusted the data analysis for sex, age, initial randomization group, and baseline T2 lesion scores to relate season-adjusted serum 25(OH)D levels to MS outcomes.

High Vitamin D Levels Predicted Reduced Disease Activity
Most patients had a vitamin D level lower than 50 nmol/L, said Dr. Ascherio. At baseline, the number of T2 lesions was higher in patients with vitamin D deficiency than in patients with sufficient vitamin D. Higher 25(OH)D levels were correlated with slower conversion from CIS to MS, reduced MS activity, and a slower rate of progression. The associations were stronger when the researchers used seasonally asynchronous blood samples to assess long-term average 25(OH)D levels.

A 50-nmol/L increment in average serum 25(OH)D levels at 12 months predicted a 57% lower rate of new active lesions, a 57% lower relapse rate, a 25% lower increase in T2 lesion volume, and a 0.41% lower annual loss of brain volume from 12 to 60 months. Compared with serum 25(OH)D levels lower than 50 nmol/L at 12 months, serum 25(OH)D levels of 50 nmol/L or more at 12 months predicted fewer active lesions on MRI, a lower increase in T2 lesion volume, a lower rate of brain loss, and lower disability, as measured by Expanded Disability Status Scale score, during the following four years.

Patient Population Was Ethnically Homogeneous
Dr. Ascherio identified several limitations to the study. Almost all of the patients were Caucasians of European ancestry, so the researchers did not draw conclusions about patients of other ethnicities. In addition, most patients eventually were treated with interferon beta, so it is unclear whether the association between disease activity and vitamin D results from an additive effect of interferon beta and vitamin D. It also is uncertain whether researchers would observe a similar beneficial effect of vitamin D in patients treated with other disease-modifying therapies.

Dr. Ascherio’s group did not see a ceiling effect of vitamin D, so it is unclear whether vitamin D supplementation would provide additional benefit to the patients. A prospective trial could give more definitive information about the therapeutic value of increasing vitamin D levels in patients with sufficient vitamin D. Neurologists should strongly consider the detection and treatment of vitamin D insufficiency and deficiency, Dr. Ascherio concluded.

—Erik Greb
Senior Associate Editor

COPENHAGEN—Serum vitamin D level early in the course of multiple sclerosis (MS) may predict a patient’s rate of long-term progression, according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Vitamin D level appears to have an inverse correlation with the number of relapses, the amount of MRI activity, the number of new active lesions, and the amount of brain atrophy over five years.

The study results suggest that vitamin D supplementation may have a role in the early treatment of MS, particularly for patients who have vitamin D insufficiency or deficiency, said Alberto Ascherio, MD, Professor of Epidemiology and Nutrition at the Harvard School of Public Health in Boston. For the purposes of the study, a serum vitamin D level of 50 nmol/L or higher was considered sufficient.

The BENEFIT Trial
To determine whether serum vitamin D levels predict disease activity after clinically isolated syndrome (CIS), Dr. Ascherio and colleagues examined data from the BENEFIT study, a randomized trial that compared the effects of early and delayed treatment with interferon beta-1b in patients with CIS. A total of 468 patients were randomized. The BENEFIT investigators measured participants’ serum 25(OH)D concentrations at baseline, six months, 12 months, and 24 months and performed clinical and MRI assessments at established intervals. At 24 months, patients entered the trial’s open phase and were offered treatment with interferon beta. Clinical and MRI follow-up lasted for five years.

Dr. Ascherio and colleagues created Cox proportional hazard models or generalized mixed effects models to analyze the data. They adjusted the data analysis for sex, age, initial randomization group, and baseline T2 lesion scores to relate season-adjusted serum 25(OH)D levels to MS outcomes.

High Vitamin D Levels Predicted Reduced Disease Activity
Most patients had a vitamin D level lower than 50 nmol/L, said Dr. Ascherio. At baseline, the number of T2 lesions was higher in patients with vitamin D deficiency than in patients with sufficient vitamin D. Higher 25(OH)D levels were correlated with slower conversion from CIS to MS, reduced MS activity, and a slower rate of progression. The associations were stronger when the researchers used seasonally asynchronous blood samples to assess long-term average 25(OH)D levels.

A 50-nmol/L increment in average serum 25(OH)D levels at 12 months predicted a 57% lower rate of new active lesions, a 57% lower relapse rate, a 25% lower increase in T2 lesion volume, and a 0.41% lower annual loss of brain volume from 12 to 60 months. Compared with serum 25(OH)D levels lower than 50 nmol/L at 12 months, serum 25(OH)D levels of 50 nmol/L or more at 12 months predicted fewer active lesions on MRI, a lower increase in T2 lesion volume, a lower rate of brain loss, and lower disability, as measured by Expanded Disability Status Scale score, during the following four years.

Patient Population Was Ethnically Homogeneous
Dr. Ascherio identified several limitations to the study. Almost all of the patients were Caucasians of European ancestry, so the researchers did not draw conclusions about patients of other ethnicities. In addition, most patients eventually were treated with interferon beta, so it is unclear whether the association between disease activity and vitamin D results from an additive effect of interferon beta and vitamin D. It also is uncertain whether researchers would observe a similar beneficial effect of vitamin D in patients treated with other disease-modifying therapies.

Dr. Ascherio’s group did not see a ceiling effect of vitamin D, so it is unclear whether vitamin D supplementation would provide additional benefit to the patients. A prospective trial could give more definitive information about the therapeutic value of increasing vitamin D levels in patients with sufficient vitamin D. Neurologists should strongly consider the detection and treatment of vitamin D insufficiency and deficiency, Dr. Ascherio concluded.

—Erik Greb
Senior Associate Editor

COPENHAGEN—Serum vitamin D level early in the course of multiple sclerosis (MS) may predict a patient’s rate of long-term progression, according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Vitamin D level appears to have an inverse correlation with the number of relapses, the amount of MRI activity, the number of new active lesions, and the amount of brain atrophy over five years.

The study results suggest that vitamin D supplementation may have a role in the early treatment of MS, particularly for patients who have vitamin D insufficiency or deficiency, said Alberto Ascherio, MD, Professor of Epidemiology and Nutrition at the Harvard School of Public Health in Boston. For the purposes of the study, a serum vitamin D level of 50 nmol/L or higher was considered sufficient.

The BENEFIT Trial
To determine whether serum vitamin D levels predict disease activity after clinically isolated syndrome (CIS), Dr. Ascherio and colleagues examined data from the BENEFIT study, a randomized trial that compared the effects of early and delayed treatment with interferon beta-1b in patients with CIS. A total of 468 patients were randomized. The BENEFIT investigators measured participants’ serum 25(OH)D concentrations at baseline, six months, 12 months, and 24 months and performed clinical and MRI assessments at established intervals. At 24 months, patients entered the trial’s open phase and were offered treatment with interferon beta. Clinical and MRI follow-up lasted for five years.

Dr. Ascherio and colleagues created Cox proportional hazard models or generalized mixed effects models to analyze the data. They adjusted the data analysis for sex, age, initial randomization group, and baseline T2 lesion scores to relate season-adjusted serum 25(OH)D levels to MS outcomes.

High Vitamin D Levels Predicted Reduced Disease Activity
Most patients had a vitamin D level lower than 50 nmol/L, said Dr. Ascherio. At baseline, the number of T2 lesions was higher in patients with vitamin D deficiency than in patients with sufficient vitamin D. Higher 25(OH)D levels were correlated with slower conversion from CIS to MS, reduced MS activity, and a slower rate of progression. The associations were stronger when the researchers used seasonally asynchronous blood samples to assess long-term average 25(OH)D levels.

A 50-nmol/L increment in average serum 25(OH)D levels at 12 months predicted a 57% lower rate of new active lesions, a 57% lower relapse rate, a 25% lower increase in T2 lesion volume, and a 0.41% lower annual loss of brain volume from 12 to 60 months. Compared with serum 25(OH)D levels lower than 50 nmol/L at 12 months, serum 25(OH)D levels of 50 nmol/L or more at 12 months predicted fewer active lesions on MRI, a lower increase in T2 lesion volume, a lower rate of brain loss, and lower disability, as measured by Expanded Disability Status Scale score, during the following four years.

Patient Population Was Ethnically Homogeneous
Dr. Ascherio identified several limitations to the study. Almost all of the patients were Caucasians of European ancestry, so the researchers did not draw conclusions about patients of other ethnicities. In addition, most patients eventually were treated with interferon beta, so it is unclear whether the association between disease activity and vitamin D results from an additive effect of interferon beta and vitamin D. It also is uncertain whether researchers would observe a similar beneficial effect of vitamin D in patients treated with other disease-modifying therapies.

Dr. Ascherio’s group did not see a ceiling effect of vitamin D, so it is unclear whether vitamin D supplementation would provide additional benefit to the patients. A prospective trial could give more definitive information about the therapeutic value of increasing vitamin D levels in patients with sufficient vitamin D. Neurologists should strongly consider the detection and treatment of vitamin D insufficiency and deficiency, Dr. Ascherio concluded.

—Erik Greb
Senior Associate Editor

COPENHAGEN—Long walking capacity tests and the Multiple Sclerosis (MS) Walking Scale-12 may be more appropriate than short walking tests (eg, the Timed 25-Foot walk) in detecting clinically meaningful improvement after rehabilitation, according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

In addition, walking capacity measures, but not the MS Walking Scale-12, may be more sensitive in detecting change in mildly disabled individuals than in moderately to severely disabled individuals with MS, said Ilse Baert, PhD, post-doctoral researcher in rehabilitation at Hasselt University in Diepenbeek, Belgium.

Patients Assessed Before and After Rehabilitation
To gauge the comparative responsiveness of five walking measures for patients with MS, Dr. Baert and colleagues performed a study at 17 centers in nine countries participating in the European Rehabilitation in MS network for best practices and research. The researchers categorized 290 patients with MS into two subgroups. Patients in the mild disability subgroup had Expanded Disability Status Scale (EDSS) scores of 4 or lower, and patients in the moderate to severe disability subgroup had EDSS scores greater than 4.

At baseline, the investigators assessed participants using the Timed 25-Foot Walk at usual speed, the Timed 25-Foot Walk at a fast speed, a two-minute walk test, a six-minute walk test, and the MS Walking Scale-12. Patients subsequently underwent a rehabilitation program that lasted between three weeks and three months. The researchers assessed patients with all five walking tests again after rehabilitation.

A clinical global impression of change scale, from patients’ and therapists’ perspectives, was chosen as an external criterion for determining responsiveness. To compare the responsiveness of the walking scales, Dr. Baert’s group calculated the area under the receiver operating characteristic curve. An outcome measure was considered not to be responsive if this value was less than 0.5. To provide reference values for clinically meaningful improvement, the researchers calculated the minimally important change, defined as the mean change score in patients who showed a minimally important change according to the external criterion. To quantify the real change (ie, measurement error), the group calculated the smallest real change.

Responsiveness and Clinically Meaningful Changes of Walking Measures
All participants had significantly better walking performance after rehabilitation, regardless of their disability levels. Overall, the MS Walking Scale-12 was the most responsive test, followed by, in order of decreasing responsiveness, the six-minute walk test, the two-minute walk test, the Timed 25-Foot Walk at fast speed, and the Timed 25-Foot Walk at usual speed.

In the mild disability subgroup, the rank of responsiveness of walking tests depended on the perspective. From the patients’ perspective, the two- and six-minute walk tests were more responsive than the Timed 25-Foot Walk test and the MS Walking Scale-12. From the therapists’ perspective, the MS Walking Scale-12 was the most responsive, followed by the Timed 25-Foot Walk at fast speed, the two- and six-minute walk tests, and the Timed 25-Foot Walk at usual speed. In the moderate to severe disability subgroup, the MS Walking Scale-12 and long walking capacity tests were more responsive than short walking tests from the patients’ and therapists’ perspectives.

The investigators found clinically meaningful differences after rehabilitation for three tests. For the two-minute walk test, improvements were 9.6 m from the patients’ perspective and 6.8 m from the therapists’ perspective. For the six-minute walk test, improvement was 21.6 m from the patients’ perspective. Scores on the MS Walking Scale-12 decreased by 10.4 from the patients’ perspective and by 11.4 from the therapists’ perspective. These clinically meaningful improvements exceeded measurement error.

—Erik Greb
Senior Associate Editor

COPENHAGEN—Long walking capacity tests and the Multiple Sclerosis (MS) Walking Scale-12 may be more appropriate than short walking tests (eg, the Timed 25-Foot walk) in detecting clinically meaningful improvement after rehabilitation, according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

In addition, walking capacity measures, but not the MS Walking Scale-12, may be more sensitive in detecting change in mildly disabled individuals than in moderately to severely disabled individuals with MS, said Ilse Baert, PhD, post-doctoral researcher in rehabilitation at Hasselt University in Diepenbeek, Belgium.

Patients Assessed Before and After Rehabilitation
To gauge the comparative responsiveness of five walking measures for patients with MS, Dr. Baert and colleagues performed a study at 17 centers in nine countries participating in the European Rehabilitation in MS network for best practices and research. The researchers categorized 290 patients with MS into two subgroups. Patients in the mild disability subgroup had Expanded Disability Status Scale (EDSS) scores of 4 or lower, and patients in the moderate to severe disability subgroup had EDSS scores greater than 4.

At baseline, the investigators assessed participants using the Timed 25-Foot Walk at usual speed, the Timed 25-Foot Walk at a fast speed, a two-minute walk test, a six-minute walk test, and the MS Walking Scale-12. Patients subsequently underwent a rehabilitation program that lasted between three weeks and three months. The researchers assessed patients with all five walking tests again after rehabilitation.

A clinical global impression of change scale, from patients’ and therapists’ perspectives, was chosen as an external criterion for determining responsiveness. To compare the responsiveness of the walking scales, Dr. Baert’s group calculated the area under the receiver operating characteristic curve. An outcome measure was considered not to be responsive if this value was less than 0.5. To provide reference values for clinically meaningful improvement, the researchers calculated the minimally important change, defined as the mean change score in patients who showed a minimally important change according to the external criterion. To quantify the real change (ie, measurement error), the group calculated the smallest real change.

Responsiveness and Clinically Meaningful Changes of Walking Measures
All participants had significantly better walking performance after rehabilitation, regardless of their disability levels. Overall, the MS Walking Scale-12 was the most responsive test, followed by, in order of decreasing responsiveness, the six-minute walk test, the two-minute walk test, the Timed 25-Foot Walk at fast speed, and the Timed 25-Foot Walk at usual speed.

In the mild disability subgroup, the rank of responsiveness of walking tests depended on the perspective. From the patients’ perspective, the two- and six-minute walk tests were more responsive than the Timed 25-Foot Walk test and the MS Walking Scale-12. From the therapists’ perspective, the MS Walking Scale-12 was the most responsive, followed by the Timed 25-Foot Walk at fast speed, the two- and six-minute walk tests, and the Timed 25-Foot Walk at usual speed. In the moderate to severe disability subgroup, the MS Walking Scale-12 and long walking capacity tests were more responsive than short walking tests from the patients’ and therapists’ perspectives.

The investigators found clinically meaningful differences after rehabilitation for three tests. For the two-minute walk test, improvements were 9.6 m from the patients’ perspective and 6.8 m from the therapists’ perspective. For the six-minute walk test, improvement was 21.6 m from the patients’ perspective. Scores on the MS Walking Scale-12 decreased by 10.4 from the patients’ perspective and by 11.4 from the therapists’ perspective. These clinically meaningful improvements exceeded measurement error.

—Erik Greb
Senior Associate Editor

COPENHAGEN—Long walking capacity tests and the Multiple Sclerosis (MS) Walking Scale-12 may be more appropriate than short walking tests (eg, the Timed 25-Foot walk) in detecting clinically meaningful improvement after rehabilitation, according to research presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

In addition, walking capacity measures, but not the MS Walking Scale-12, may be more sensitive in detecting change in mildly disabled individuals than in moderately to severely disabled individuals with MS, said Ilse Baert, PhD, post-doctoral researcher in rehabilitation at Hasselt University in Diepenbeek, Belgium.

Patients Assessed Before and After Rehabilitation
To gauge the comparative responsiveness of five walking measures for patients with MS, Dr. Baert and colleagues performed a study at 17 centers in nine countries participating in the European Rehabilitation in MS network for best practices and research. The researchers categorized 290 patients with MS into two subgroups. Patients in the mild disability subgroup had Expanded Disability Status Scale (EDSS) scores of 4 or lower, and patients in the moderate to severe disability subgroup had EDSS scores greater than 4.

At baseline, the investigators assessed participants using the Timed 25-Foot Walk at usual speed, the Timed 25-Foot Walk at a fast speed, a two-minute walk test, a six-minute walk test, and the MS Walking Scale-12. Patients subsequently underwent a rehabilitation program that lasted between three weeks and three months. The researchers assessed patients with all five walking tests again after rehabilitation.

A clinical global impression of change scale, from patients’ and therapists’ perspectives, was chosen as an external criterion for determining responsiveness. To compare the responsiveness of the walking scales, Dr. Baert’s group calculated the area under the receiver operating characteristic curve. An outcome measure was considered not to be responsive if this value was less than 0.5. To provide reference values for clinically meaningful improvement, the researchers calculated the minimally important change, defined as the mean change score in patients who showed a minimally important change according to the external criterion. To quantify the real change (ie, measurement error), the group calculated the smallest real change.

Responsiveness and Clinically Meaningful Changes of Walking Measures
All participants had significantly better walking performance after rehabilitation, regardless of their disability levels. Overall, the MS Walking Scale-12 was the most responsive test, followed by, in order of decreasing responsiveness, the six-minute walk test, the two-minute walk test, the Timed 25-Foot Walk at fast speed, and the Timed 25-Foot Walk at usual speed.

In the mild disability subgroup, the rank of responsiveness of walking tests depended on the perspective. From the patients’ perspective, the two- and six-minute walk tests were more responsive than the Timed 25-Foot Walk test and the MS Walking Scale-12. From the therapists’ perspective, the MS Walking Scale-12 was the most responsive, followed by the Timed 25-Foot Walk at fast speed, the two- and six-minute walk tests, and the Timed 25-Foot Walk at usual speed. In the moderate to severe disability subgroup, the MS Walking Scale-12 and long walking capacity tests were more responsive than short walking tests from the patients’ and therapists’ perspectives.

The investigators found clinically meaningful differences after rehabilitation for three tests. For the two-minute walk test, improvements were 9.6 m from the patients’ perspective and 6.8 m from the therapists’ perspective. For the six-minute walk test, improvement was 21.6 m from the patients’ perspective. Scores on the MS Walking Scale-12 decreased by 10.4 from the patients’ perspective and by 11.4 from the therapists’ perspective. These clinically meaningful improvements exceeded measurement error.

—Erik Greb
Senior Associate Editor

Gray matter, rather than myelin, may be involved in the earliest stages of multiple sclerosis (MS), according to research published September 3 in PLOS One. Gray matter components (eg, axons, neurons, and synapses) may distinguish the CSF proteome of a patient with a true first attack of MS from those of healthy controls and patients with established relapsing-remitting MS.

Nogo receptor was markedly elevated in the CSF of patients with a true first attack of MS, compared with patients with established relapsing-remitting MS and controls, said Steven E. Schutzer, MD, Professor of Medicine at Rutgers University New Jersey Medical School in Newark. Patients with a first attack of MS also had a significant increase of contactin-2/TAG-1, an axonal glycoprotein, in their CSF. Contactin-2/TAG-1 has been reported as an autoimmune target in MS.

Researchers Analyzed CSF From Three Patient Groups
Previous imaging studies have suggested that gray matter changes, and not white matter changes, occur early and predict the development of MS. Other data have conflicted with this idea, however. To determine whether gray matter is involved in early MS, Dr. Schutzer and colleagues collected CSF from three groups of patients. The first group included nine patients with clinically isolated syndrome (CIS) who eventually met diagnostic criteria for MS. The second group included 12 patients with established diagnoses of relapsing-remitting MS according to the McDonald criteria. The third group included six control subjects with no apparent CNS disease.

For the purpose of comparison, the investigators used previously published protein lists generated from two groups of persons with other neurologic diseases and more than 200 healthy controls. The researchers also analyzed a separate group of 10 patients with CIS to compare them with the CIS patients in the study. Dr. Schutzer and colleagues performed protein separation and fractionation on the CSF samples and analyzed them with direct liquid chromatography–mass spectrometry.

Quantities of 20 Proteins Differed Among the Groups
The researchers found 20 proteins that were present in significantly different quantities in patients with CIS, patients with established relapsing-remitting MS, and controls. Nine of these proteins were significantly increased in patients with first-attack CIS, compared with the other two groups. Five proteins were significantly decreased in patients with first-attack CIS, compared with the other groups. The remaining proteins were increased in patients with CIS, compared with patients with relapsing-remitting MS, but decreased compared with controls. Fifteen of the 20 proteins were associated with gray matter.

“There is an increasing literature on the importance of gray matter, neuronal, and axonal involvement in MS, even at very early time points,” said Dr. Schutzer. “Our findings support this [hypothesis] and indicate that axonal, neuronal, and synaptic involvement may be required for the initial presentation of MS. It is interesting in this disease, which is characterized by demyelination as it progresses, that gray matter components may be diagnostically more useful than myelin components at the earliest stages,” he added.

—Erik Greb
Senior Associate Editor

Gray matter, rather than myelin, may be involved in the earliest stages of multiple sclerosis (MS), according to research published September 3 in PLOS One. Gray matter components (eg, axons, neurons, and synapses) may distinguish the CSF proteome of a patient with a true first attack of MS from those of healthy controls and patients with established relapsing-remitting MS.

Nogo receptor was markedly elevated in the CSF of patients with a true first attack of MS, compared with patients with established relapsing-remitting MS and controls, said Steven E. Schutzer, MD, Professor of Medicine at Rutgers University New Jersey Medical School in Newark. Patients with a first attack of MS also had a significant increase of contactin-2/TAG-1, an axonal glycoprotein, in their CSF. Contactin-2/TAG-1 has been reported as an autoimmune target in MS.

Researchers Analyzed CSF From Three Patient Groups
Previous imaging studies have suggested that gray matter changes, and not white matter changes, occur early and predict the development of MS. Other data have conflicted with this idea, however. To determine whether gray matter is involved in early MS, Dr. Schutzer and colleagues collected CSF from three groups of patients. The first group included nine patients with clinically isolated syndrome (CIS) who eventually met diagnostic criteria for MS. The second group included 12 patients with established diagnoses of relapsing-remitting MS according to the McDonald criteria. The third group included six control subjects with no apparent CNS disease.

For the purpose of comparison, the investigators used previously published protein lists generated from two groups of persons with other neurologic diseases and more than 200 healthy controls. The researchers also analyzed a separate group of 10 patients with CIS to compare them with the CIS patients in the study. Dr. Schutzer and colleagues performed protein separation and fractionation on the CSF samples and analyzed them with direct liquid chromatography–mass spectrometry.

Quantities of 20 Proteins Differed Among the Groups
The researchers found 20 proteins that were present in significantly different quantities in patients with CIS, patients with established relapsing-remitting MS, and controls. Nine of these proteins were significantly increased in patients with first-attack CIS, compared with the other two groups. Five proteins were significantly decreased in patients with first-attack CIS, compared with the other groups. The remaining proteins were increased in patients with CIS, compared with patients with relapsing-remitting MS, but decreased compared with controls. Fifteen of the 20 proteins were associated with gray matter.

“There is an increasing literature on the importance of gray matter, neuronal, and axonal involvement in MS, even at very early time points,” said Dr. Schutzer. “Our findings support this [hypothesis] and indicate that axonal, neuronal, and synaptic involvement may be required for the initial presentation of MS. It is interesting in this disease, which is characterized by demyelination as it progresses, that gray matter components may be diagnostically more useful than myelin components at the earliest stages,” he added.

—Erik Greb
Senior Associate Editor

Gray matter, rather than myelin, may be involved in the earliest stages of multiple sclerosis (MS), according to research published September 3 in PLOS One. Gray matter components (eg, axons, neurons, and synapses) may distinguish the CSF proteome of a patient with a true first attack of MS from those of healthy controls and patients with established relapsing-remitting MS.

Nogo receptor was markedly elevated in the CSF of patients with a true first attack of MS, compared with patients with established relapsing-remitting MS and controls, said Steven E. Schutzer, MD, Professor of Medicine at Rutgers University New Jersey Medical School in Newark. Patients with a first attack of MS also had a significant increase of contactin-2/TAG-1, an axonal glycoprotein, in their CSF. Contactin-2/TAG-1 has been reported as an autoimmune target in MS.

Researchers Analyzed CSF From Three Patient Groups
Previous imaging studies have suggested that gray matter changes, and not white matter changes, occur early and predict the development of MS. Other data have conflicted with this idea, however. To determine whether gray matter is involved in early MS, Dr. Schutzer and colleagues collected CSF from three groups of patients. The first group included nine patients with clinically isolated syndrome (CIS) who eventually met diagnostic criteria for MS. The second group included 12 patients with established diagnoses of relapsing-remitting MS according to the McDonald criteria. The third group included six control subjects with no apparent CNS disease.

For the purpose of comparison, the investigators used previously published protein lists generated from two groups of persons with other neurologic diseases and more than 200 healthy controls. The researchers also analyzed a separate group of 10 patients with CIS to compare them with the CIS patients in the study. Dr. Schutzer and colleagues performed protein separation and fractionation on the CSF samples and analyzed them with direct liquid chromatography–mass spectrometry.

Quantities of 20 Proteins Differed Among the Groups
The researchers found 20 proteins that were present in significantly different quantities in patients with CIS, patients with established relapsing-remitting MS, and controls. Nine of these proteins were significantly increased in patients with first-attack CIS, compared with the other two groups. Five proteins were significantly decreased in patients with first-attack CIS, compared with the other groups. The remaining proteins were increased in patients with CIS, compared with patients with relapsing-remitting MS, but decreased compared with controls. Fifteen of the 20 proteins were associated with gray matter.

“There is an increasing literature on the importance of gray matter, neuronal, and axonal involvement in MS, even at very early time points,” said Dr. Schutzer. “Our findings support this [hypothesis] and indicate that axonal, neuronal, and synaptic involvement may be required for the initial presentation of MS. It is interesting in this disease, which is characterized by demyelination as it progresses, that gray matter components may be diagnostically more useful than myelin components at the earliest stages,” he added.

—Erik Greb
Senior Associate Editor

In a small but well-designed study, Schutzer et al used high-resolution mass spectrometry to compare CSF proteins in patients with clinically isolated syndrome (CIS) who eventually developed multiple sclerosis (MS), patients with established relapsing-remitting MS, and controls with no obvious neurologic disease. CSF proteins from patients with CIS were differentially enriched for gray matter components (eg, axons, neurons, and synapses), compared with other groups.

The prominence of gray matter CSF proteins early in MS evolution is not surprising. Sophisticated MRI techniques have allowed investigators to describe gray matter lesions as an early phenomenon in MS, and these lesions may even be more prominent than white matter lesions. Cerebral gray matter is active metabolically; it has greater blood flow, oxygen consumption, and tissue volume than white matter. Axonal pathology is an early and common finding in MS, even in apparently normal white matter, possibly because of immune-mediated inflammatory damage and associated Wallerian degeneration. In addition, gray matter MS pathology can be seen adjacent to meningeal inflammation, and oligodendrocytes and myelinated axons are present in gray matter. These findings are consistent with diffusion of CSF-reactive lymphocytes or their products into cerebral gray matter, and a similar mechanism may occur in white matter across the blood–brain barrier.

However, the concept that CSF gray matter proteins are more enriched in patients with CIS than in those with established MS comes as somewhat of a surprise. While patients with CIS have had only one clinically documented event, there are usually multiple brain lesions that are clinically silent but detected on MRI. These can be considered subclinical relapses because the lesions occur in less eloquent areas or are less destructive. Thus, one does not usually know with certainty when MS actually starts. In this regard, it would be interesting to obtain information on gray matter proteins after a second spinal tap in patients with CIS who later develop definite MS.

Lastly, although gray matter may be affected early in MS, there is insufficient evidence as to whether or not a gray matter protein is an autoimmune trigger in MS.

—Stuart D. Cook, MD
Ruth Dunietz Kushner and Michael Jay Serwitz Professor
of Neurology and Neurosciences
Rutgers, The State University of New Jersey, Newark

In a small but well-designed study, Schutzer et al used high-resolution mass spectrometry to compare CSF proteins in patients with clinically isolated syndrome (CIS) who eventually developed multiple sclerosis (MS), patients with established relapsing-remitting MS, and controls with no obvious neurologic disease. CSF proteins from patients with CIS were differentially enriched for gray matter components (eg, axons, neurons, and synapses), compared with other groups.

The prominence of gray matter CSF proteins early in MS evolution is not surprising. Sophisticated MRI techniques have allowed investigators to describe gray matter lesions as an early phenomenon in MS, and these lesions may even be more prominent than white matter lesions. Cerebral gray matter is active metabolically; it has greater blood flow, oxygen consumption, and tissue volume than white matter. Axonal pathology is an early and common finding in MS, even in apparently normal white matter, possibly because of immune-mediated inflammatory damage and associated Wallerian degeneration. In addition, gray matter MS pathology can be seen adjacent to meningeal inflammation, and oligodendrocytes and myelinated axons are present in gray matter. These findings are consistent with diffusion of CSF-reactive lymphocytes or their products into cerebral gray matter, and a similar mechanism may occur in white matter across the blood–brain barrier.

However, the concept that CSF gray matter proteins are more enriched in patients with CIS than in those with established MS comes as somewhat of a surprise. While patients with CIS have had only one clinically documented event, there are usually multiple brain lesions that are clinically silent but detected on MRI. These can be considered subclinical relapses because the lesions occur in less eloquent areas or are less destructive. Thus, one does not usually know with certainty when MS actually starts. In this regard, it would be interesting to obtain information on gray matter proteins after a second spinal tap in patients with CIS who later develop definite MS.

Lastly, although gray matter may be affected early in MS, there is insufficient evidence as to whether or not a gray matter protein is an autoimmune trigger in MS.

—Stuart D. Cook, MD
Ruth Dunietz Kushner and Michael Jay Serwitz Professor
of Neurology and Neurosciences
Rutgers, The State University of New Jersey, Newark

In a small but well-designed study, Schutzer et al used high-resolution mass spectrometry to compare CSF proteins in patients with clinically isolated syndrome (CIS) who eventually developed multiple sclerosis (MS), patients with established relapsing-remitting MS, and controls with no obvious neurologic disease. CSF proteins from patients with CIS were differentially enriched for gray matter components (eg, axons, neurons, and synapses), compared with other groups.

The prominence of gray matter CSF proteins early in MS evolution is not surprising. Sophisticated MRI techniques have allowed investigators to describe gray matter lesions as an early phenomenon in MS, and these lesions may even be more prominent than white matter lesions. Cerebral gray matter is active metabolically; it has greater blood flow, oxygen consumption, and tissue volume than white matter. Axonal pathology is an early and common finding in MS, even in apparently normal white matter, possibly because of immune-mediated inflammatory damage and associated Wallerian degeneration. In addition, gray matter MS pathology can be seen adjacent to meningeal inflammation, and oligodendrocytes and myelinated axons are present in gray matter. These findings are consistent with diffusion of CSF-reactive lymphocytes or their products into cerebral gray matter, and a similar mechanism may occur in white matter across the blood–brain barrier.

However, the concept that CSF gray matter proteins are more enriched in patients with CIS than in those with established MS comes as somewhat of a surprise. While patients with CIS have had only one clinically documented event, there are usually multiple brain lesions that are clinically silent but detected on MRI. These can be considered subclinical relapses because the lesions occur in less eloquent areas or are less destructive. Thus, one does not usually know with certainty when MS actually starts. In this regard, it would be interesting to obtain information on gray matter proteins after a second spinal tap in patients with CIS who later develop definite MS.

Lastly, although gray matter may be affected early in MS, there is insufficient evidence as to whether or not a gray matter protein is an autoimmune trigger in MS.

—Stuart D. Cook, MD
Ruth Dunietz Kushner and Michael Jay Serwitz Professor
of Neurology and Neurosciences
Rutgers, The State University of New Jersey, Newark

COPENHAGEN—Most, if not all, of the previous claims for association between multiple sclerosis (MS) and month of birth are false positive, according to a study presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). According to researchers, the reported association is more likely to have arisen through confounding factors rather than biology.

Barnaby D. Fiddes, MD, from the Department of Clinical Neurosciences at the University of Cambridge, and colleagues recognized that association studies can generate false positive results if cases and controls are not adequately matched for confounding variables. Given how heterogeneous month of birth is with respect to both year and place of birth, the researchers investigated whether uncompensated variables might underlie the previously reported association between MS and month of birth.

The researchers used publicly available national records for 271 million births in the United Kingdom and Europe to establish birth rates in the general population and their own databases of patients with MS to establish the age and regional origin distribution seen in a typical MS case collection. The investigators also used simulations to make a highly conservative estimate of the false positive rate expected in an analysis of month of birth following the approach used in previously published studies that showed an association between MS and month of birth.

Dr. Fiddes and his research colleagues confirmed that month of birth in the general population shows marked seasonal variation and that this seasonality is highly heterogeneous over time and both between and within countries. Simulations based on UK Government Office Region data showed that failing to correct for within-population variations in month of birth results in a high probability of false positive association.

“We confirmed that in spring months, birth rate shows a positive correlation with latitude and a negative correlation with year of birth, while the reverse is true in winter months,” the researchers reported. “These correlations explain the superficial consistency between month-of-birth studies.”

Dr. Fiddes and colleagues concluded that “although it is impossible to completely exclude any possibility of a month-of-birth effect, our data indicate that previous claims of association between month of birth and MS are almost certain to be false positives.”

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Most, if not all, of the previous claims for association between multiple sclerosis (MS) and month of birth are false positive, according to a study presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). According to researchers, the reported association is more likely to have arisen through confounding factors rather than biology.

Barnaby D. Fiddes, MD, from the Department of Clinical Neurosciences at the University of Cambridge, and colleagues recognized that association studies can generate false positive results if cases and controls are not adequately matched for confounding variables. Given how heterogeneous month of birth is with respect to both year and place of birth, the researchers investigated whether uncompensated variables might underlie the previously reported association between MS and month of birth.

The researchers used publicly available national records for 271 million births in the United Kingdom and Europe to establish birth rates in the general population and their own databases of patients with MS to establish the age and regional origin distribution seen in a typical MS case collection. The investigators also used simulations to make a highly conservative estimate of the false positive rate expected in an analysis of month of birth following the approach used in previously published studies that showed an association between MS and month of birth.

Dr. Fiddes and his research colleagues confirmed that month of birth in the general population shows marked seasonal variation and that this seasonality is highly heterogeneous over time and both between and within countries. Simulations based on UK Government Office Region data showed that failing to correct for within-population variations in month of birth results in a high probability of false positive association.

“We confirmed that in spring months, birth rate shows a positive correlation with latitude and a negative correlation with year of birth, while the reverse is true in winter months,” the researchers reported. “These correlations explain the superficial consistency between month-of-birth studies.”

Dr. Fiddes and colleagues concluded that “although it is impossible to completely exclude any possibility of a month-of-birth effect, our data indicate that previous claims of association between month of birth and MS are almost certain to be false positives.”

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Most, if not all, of the previous claims for association between multiple sclerosis (MS) and month of birth are false positive, according to a study presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). According to researchers, the reported association is more likely to have arisen through confounding factors rather than biology.

Barnaby D. Fiddes, MD, from the Department of Clinical Neurosciences at the University of Cambridge, and colleagues recognized that association studies can generate false positive results if cases and controls are not adequately matched for confounding variables. Given how heterogeneous month of birth is with respect to both year and place of birth, the researchers investigated whether uncompensated variables might underlie the previously reported association between MS and month of birth.

The researchers used publicly available national records for 271 million births in the United Kingdom and Europe to establish birth rates in the general population and their own databases of patients with MS to establish the age and regional origin distribution seen in a typical MS case collection. The investigators also used simulations to make a highly conservative estimate of the false positive rate expected in an analysis of month of birth following the approach used in previously published studies that showed an association between MS and month of birth.

Dr. Fiddes and his research colleagues confirmed that month of birth in the general population shows marked seasonal variation and that this seasonality is highly heterogeneous over time and both between and within countries. Simulations based on UK Government Office Region data showed that failing to correct for within-population variations in month of birth results in a high probability of false positive association.

“We confirmed that in spring months, birth rate shows a positive correlation with latitude and a negative correlation with year of birth, while the reverse is true in winter months,” the researchers reported. “These correlations explain the superficial consistency between month-of-birth studies.”

Dr. Fiddes and colleagues concluded that “although it is impossible to completely exclude any possibility of a month-of-birth effect, our data indicate that previous claims of association between month of birth and MS are almost certain to be false positives.”

—Glenn S. Williams
Vice President/Group Editor

AUSTIN—The 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis (MS) may have a higher sensitivity for diagnosing pediatric MS, compared with the 2005 criteria. The revised criteria thus could allow for earlier initiation of disease-modifying therapy, researchers reported at the 2013 Annual Meeting of the Child Neurology Society.

Mitchel T. Williams, MD, Pediatric Neurologist at the Children’s Hospital of Michigan in Detroit, and colleagues conducted a retrospective study of 25 children who had been diagnosed with MS at the Children’s Hospital of Michigan from 2005 through early 2013. The researchers applied the 2005 and 2010 McDonald criteria based on neuroimaging findings and initial clinical presentation. The investigators also analyzed demographic data and compared those data with those of previous pediatric MS cohorts.

The median age at presentation, sex ratio, clinical symptoms, and relapse rate among the participants were comparable to those in previously published data, except for a high rate of African Americans (64%) among the 25 children. The researchers found that the initial MS diagnosis rate based on the 2005 McDonald criteria was 32%, compared with a rate of 92% using the 2010 McDonald criteria. The mean time after initial symptom presentation until the 2005 criteria for MS were met was 5.0 months, compared with 0.7 months for the 2010 McDonald criteria.

“[Our findings] suggest that the 2010 McDonald criteria are a more appropriate tool for the timely diagnosis of pediatric MS,” concluded the researchers.

—Colby Stong
Editor

AUSTIN—The 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis (MS) may have a higher sensitivity for diagnosing pediatric MS, compared with the 2005 criteria. The revised criteria thus could allow for earlier initiation of disease-modifying therapy, researchers reported at the 2013 Annual Meeting of the Child Neurology Society.

Mitchel T. Williams, MD, Pediatric Neurologist at the Children’s Hospital of Michigan in Detroit, and colleagues conducted a retrospective study of 25 children who had been diagnosed with MS at the Children’s Hospital of Michigan from 2005 through early 2013. The researchers applied the 2005 and 2010 McDonald criteria based on neuroimaging findings and initial clinical presentation. The investigators also analyzed demographic data and compared those data with those of previous pediatric MS cohorts.

The median age at presentation, sex ratio, clinical symptoms, and relapse rate among the participants were comparable to those in previously published data, except for a high rate of African Americans (64%) among the 25 children. The researchers found that the initial MS diagnosis rate based on the 2005 McDonald criteria was 32%, compared with a rate of 92% using the 2010 McDonald criteria. The mean time after initial symptom presentation until the 2005 criteria for MS were met was 5.0 months, compared with 0.7 months for the 2010 McDonald criteria.

“[Our findings] suggest that the 2010 McDonald criteria are a more appropriate tool for the timely diagnosis of pediatric MS,” concluded the researchers.

—Colby Stong
Editor

AUSTIN—The 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis (MS) may have a higher sensitivity for diagnosing pediatric MS, compared with the 2005 criteria. The revised criteria thus could allow for earlier initiation of disease-modifying therapy, researchers reported at the 2013 Annual Meeting of the Child Neurology Society.

Mitchel T. Williams, MD, Pediatric Neurologist at the Children’s Hospital of Michigan in Detroit, and colleagues conducted a retrospective study of 25 children who had been diagnosed with MS at the Children’s Hospital of Michigan from 2005 through early 2013. The researchers applied the 2005 and 2010 McDonald criteria based on neuroimaging findings and initial clinical presentation. The investigators also analyzed demographic data and compared those data with those of previous pediatric MS cohorts.

The median age at presentation, sex ratio, clinical symptoms, and relapse rate among the participants were comparable to those in previously published data, except for a high rate of African Americans (64%) among the 25 children. The researchers found that the initial MS diagnosis rate based on the 2005 McDonald criteria was 32%, compared with a rate of 92% using the 2010 McDonald criteria. The mean time after initial symptom presentation until the 2005 criteria for MS were met was 5.0 months, compared with 0.7 months for the 2010 McDonald criteria.

“[Our findings] suggest that the 2010 McDonald criteria are a more appropriate tool for the timely diagnosis of pediatric MS,” concluded the researchers.

—Colby Stong
Editor

COPENHAGEN—Higher sodium levels are associated with increased clinical and radiologic disease activity in patients with multiple sclerosis (MS), according to study findings presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Because salt has been recently reported to promote the differentiation of pathogenic T cells and worsen disease in an experimental model of MS, investigators sought to determine the relationship between salt consumption and MS disease clinical and radiologic activity.

Mauricio F. Farez, MD, from the Department of Neurology, Institute for Neurological Research Dr Raúl Carrea, Foundation Against Neurological Disease in childhood (FLENI), Buenos Aires, and colleagues measured sodium intake using urine samples from a cohort of 70 patients with relapsing-remitting MS who were followed for two years. During the follow-up, clinical and radiologic assessments were performed every three to six months or in the event of a relapse. The effect of sodium intake on MS disease activity was estimated by regression analysis.

The researchers found a positive correlation between exacerbation rates and sodium intake in a multivariate model adjusted for age, gender, disease duration, smoking status, vitamin D levels, BMI, and treatment. They found an exacerbation rate of 2.75 and 3.95 times higher in patients with medium and high sodium intake, respectively, when compared with the low intake group. In addition, individuals with high sodium intake had 3.4 times greater odds of developing a new lesion on MRI and, on average, had eight more T2 lesions on MRI.

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Higher sodium levels are associated with increased clinical and radiologic disease activity in patients with multiple sclerosis (MS), according to study findings presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Because salt has been recently reported to promote the differentiation of pathogenic T cells and worsen disease in an experimental model of MS, investigators sought to determine the relationship between salt consumption and MS disease clinical and radiologic activity.

Mauricio F. Farez, MD, from the Department of Neurology, Institute for Neurological Research Dr Raúl Carrea, Foundation Against Neurological Disease in childhood (FLENI), Buenos Aires, and colleagues measured sodium intake using urine samples from a cohort of 70 patients with relapsing-remitting MS who were followed for two years. During the follow-up, clinical and radiologic assessments were performed every three to six months or in the event of a relapse. The effect of sodium intake on MS disease activity was estimated by regression analysis.

The researchers found a positive correlation between exacerbation rates and sodium intake in a multivariate model adjusted for age, gender, disease duration, smoking status, vitamin D levels, BMI, and treatment. They found an exacerbation rate of 2.75 and 3.95 times higher in patients with medium and high sodium intake, respectively, when compared with the low intake group. In addition, individuals with high sodium intake had 3.4 times greater odds of developing a new lesion on MRI and, on average, had eight more T2 lesions on MRI.

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Higher sodium levels are associated with increased clinical and radiologic disease activity in patients with multiple sclerosis (MS), according to study findings presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Because salt has been recently reported to promote the differentiation of pathogenic T cells and worsen disease in an experimental model of MS, investigators sought to determine the relationship between salt consumption and MS disease clinical and radiologic activity.

Mauricio F. Farez, MD, from the Department of Neurology, Institute for Neurological Research Dr Raúl Carrea, Foundation Against Neurological Disease in childhood (FLENI), Buenos Aires, and colleagues measured sodium intake using urine samples from a cohort of 70 patients with relapsing-remitting MS who were followed for two years. During the follow-up, clinical and radiologic assessments were performed every three to six months or in the event of a relapse. The effect of sodium intake on MS disease activity was estimated by regression analysis.

The researchers found a positive correlation between exacerbation rates and sodium intake in a multivariate model adjusted for age, gender, disease duration, smoking status, vitamin D levels, BMI, and treatment. They found an exacerbation rate of 2.75 and 3.95 times higher in patients with medium and high sodium intake, respectively, when compared with the low intake group. In addition, individuals with high sodium intake had 3.4 times greater odds of developing a new lesion on MRI and, on average, had eight more T2 lesions on MRI.

—Glenn S. Williams
Vice President/Group Editor