Multiple Sclerosis

PHILADELPHIA—Ofatumumab reduces new T1 gadolinium-enhancing lesions by more than 90%, compared with placebo, among patients with relapsing-remitting multiple sclerosis (MS), according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The monoclonal antibody appears to deplete B cells in a dose-dependent manner.

Investigators found no difference between drug and placebo in the rate of adverse events, and the majority of the adverse events were mild to moderate. The most common adverse events were injection-related reactions.

Ofatumumab is a fully human anti-CD20 monoclonal antibody that binds even at low levels of CD20. The drug “induces B cell lysis quite efficiently, primarily through antibody-dependent cellular cytotoxicity,” said Amit Bar-Or, MD, Professor of Neurology and Neurosurgery at McGill University in Montreal. Ofatumumab is indicated for the treatment of chronic lymphocytic leukemia.

Comparing Doses of Ofatumumab
Dr. Bar-Or and colleagues conducted a placebo-controlled trial to determine the MRI efficacy, tolerability, and safety of subcutaneous injections of ofatumumab in patients with relapsing-remitting MS. The study’s primary end point was the cumulative number of new T1 gadolinium-enhancing brain lesions at 12 weeks.

The researchers randomized 231 individuals with relapsing-remitting MS to either placebo, 3 mg of ofatumumab every three months, 30 mg of ofatumumab every three months, 60 mg of ofatumumab every three months, or 60 mg of ofatumumab every month. The study began with a 24-week double-blind treatment phase, followed by a 20-week individualized follow-up phase. Dr. Bar-Or reported on the primary outcome as assessed at week 12.

Eligible patients were between ages 18 and 55 and had an Expanded Disability Status Scale score between 0 and 5.5. Baseline patient characteristics were well balanced among the study groups with respect to sex, race, age, and disease duration. At baseline, patients’ number of relapses within the past 24 months ranged from 1.7 to 1.9. More than 90% of participants completed the 24-week treatment phase of the study.

Ofatumumab Reduced New Lesions by More Than 90%
The dosing regimens were associated with a dose-dependent decrease in circulating B cells, and mathematical modeling indicated that a 50% decrease in B cells would be expected with a dose of less than 3 mg of ofatumumab. Individuals who received 3 mg of drug every three months had a 70% reduction in new gadolinium-enhancing lesions, relative to controls. New gadolinium-enhancing lesions in the brain were reduced by more than 90%, relative to controls, in patients who received the three dose regimens of 30 mg of ofatumumab or more.

Over the 24-week treatment phase, six adverse events led to withdrawal from the study (all of these occurring in the treatment arms). The investigators found no differences in the rate of infectious adverse events between the study groups, including placebo treated. Infectious adverse events included nasopharyngitis, urinary tract infection, and respiratory tract infection, but these outcomes were infrequent “and no different from what we have seen in prior anti-CD20–depleting regimens,” said Dr. Bar-Or.

Injection-Related Reactions Were the Most Common Adverse Events
Five individuals had serious adverse events during the first 12 weeks. Another serious adverse event occurred between weeks 12 and 24. The serious adverse events included injection-related reactions, cholelithiasis, cytokine release syndrome, and hypokalemia. Four of these events occurred in patients receiving 60 mg of ofatumumab every month.

“There was no evidence of clinically meaningful changes in laboratory parameters or vital signs,” said Dr. Bar-Or. “There was no evidence of clinically meaningful immunogenicity, including development of human antihuman antibodies, which occurred in only four individuals at low levels and did not appear to impact treatment effect. There were no cases of opportunistic infections, including progressive multifocal lleukoencephalopathy.”

—Erik Greb

PHILADELPHIA—Ofatumumab reduces new T1 gadolinium-enhancing lesions by more than 90%, compared with placebo, among patients with relapsing-remitting multiple sclerosis (MS), according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The monoclonal antibody appears to deplete B cells in a dose-dependent manner.

Investigators found no difference between drug and placebo in the rate of adverse events, and the majority of the adverse events were mild to moderate. The most common adverse events were injection-related reactions.

Ofatumumab is a fully human anti-CD20 monoclonal antibody that binds even at low levels of CD20. The drug “induces B cell lysis quite efficiently, primarily through antibody-dependent cellular cytotoxicity,” said Amit Bar-Or, MD, Professor of Neurology and Neurosurgery at McGill University in Montreal. Ofatumumab is indicated for the treatment of chronic lymphocytic leukemia.

Comparing Doses of Ofatumumab
Dr. Bar-Or and colleagues conducted a placebo-controlled trial to determine the MRI efficacy, tolerability, and safety of subcutaneous injections of ofatumumab in patients with relapsing-remitting MS. The study’s primary end point was the cumulative number of new T1 gadolinium-enhancing brain lesions at 12 weeks.

The researchers randomized 231 individuals with relapsing-remitting MS to either placebo, 3 mg of ofatumumab every three months, 30 mg of ofatumumab every three months, 60 mg of ofatumumab every three months, or 60 mg of ofatumumab every month. The study began with a 24-week double-blind treatment phase, followed by a 20-week individualized follow-up phase. Dr. Bar-Or reported on the primary outcome as assessed at week 12.

Eligible patients were between ages 18 and 55 and had an Expanded Disability Status Scale score between 0 and 5.5. Baseline patient characteristics were well balanced among the study groups with respect to sex, race, age, and disease duration. At baseline, patients’ number of relapses within the past 24 months ranged from 1.7 to 1.9. More than 90% of participants completed the 24-week treatment phase of the study.

Ofatumumab Reduced New Lesions by More Than 90%
The dosing regimens were associated with a dose-dependent decrease in circulating B cells, and mathematical modeling indicated that a 50% decrease in B cells would be expected with a dose of less than 3 mg of ofatumumab. Individuals who received 3 mg of drug every three months had a 70% reduction in new gadolinium-enhancing lesions, relative to controls. New gadolinium-enhancing lesions in the brain were reduced by more than 90%, relative to controls, in patients who received the three dose regimens of 30 mg of ofatumumab or more.

Over the 24-week treatment phase, six adverse events led to withdrawal from the study (all of these occurring in the treatment arms). The investigators found no differences in the rate of infectious adverse events between the study groups, including placebo treated. Infectious adverse events included nasopharyngitis, urinary tract infection, and respiratory tract infection, but these outcomes were infrequent “and no different from what we have seen in prior anti-CD20–depleting regimens,” said Dr. Bar-Or.

Injection-Related Reactions Were the Most Common Adverse Events
Five individuals had serious adverse events during the first 12 weeks. Another serious adverse event occurred between weeks 12 and 24. The serious adverse events included injection-related reactions, cholelithiasis, cytokine release syndrome, and hypokalemia. Four of these events occurred in patients receiving 60 mg of ofatumumab every month.

“There was no evidence of clinically meaningful changes in laboratory parameters or vital signs,” said Dr. Bar-Or. “There was no evidence of clinically meaningful immunogenicity, including development of human antihuman antibodies, which occurred in only four individuals at low levels and did not appear to impact treatment effect. There were no cases of opportunistic infections, including progressive multifocal lleukoencephalopathy.”

—Erik Greb

PHILADELPHIA—Ofatumumab reduces new T1 gadolinium-enhancing lesions by more than 90%, compared with placebo, among patients with relapsing-remitting multiple sclerosis (MS), according to research presented at the 66th Annual Meeting of the American Academy of Neurology. The monoclonal antibody appears to deplete B cells in a dose-dependent manner.

Investigators found no difference between drug and placebo in the rate of adverse events, and the majority of the adverse events were mild to moderate. The most common adverse events were injection-related reactions.

Ofatumumab is a fully human anti-CD20 monoclonal antibody that binds even at low levels of CD20. The drug “induces B cell lysis quite efficiently, primarily through antibody-dependent cellular cytotoxicity,” said Amit Bar-Or, MD, Professor of Neurology and Neurosurgery at McGill University in Montreal. Ofatumumab is indicated for the treatment of chronic lymphocytic leukemia.

Comparing Doses of Ofatumumab
Dr. Bar-Or and colleagues conducted a placebo-controlled trial to determine the MRI efficacy, tolerability, and safety of subcutaneous injections of ofatumumab in patients with relapsing-remitting MS. The study’s primary end point was the cumulative number of new T1 gadolinium-enhancing brain lesions at 12 weeks.

The researchers randomized 231 individuals with relapsing-remitting MS to either placebo, 3 mg of ofatumumab every three months, 30 mg of ofatumumab every three months, 60 mg of ofatumumab every three months, or 60 mg of ofatumumab every month. The study began with a 24-week double-blind treatment phase, followed by a 20-week individualized follow-up phase. Dr. Bar-Or reported on the primary outcome as assessed at week 12.

Eligible patients were between ages 18 and 55 and had an Expanded Disability Status Scale score between 0 and 5.5. Baseline patient characteristics were well balanced among the study groups with respect to sex, race, age, and disease duration. At baseline, patients’ number of relapses within the past 24 months ranged from 1.7 to 1.9. More than 90% of participants completed the 24-week treatment phase of the study.

Ofatumumab Reduced New Lesions by More Than 90%
The dosing regimens were associated with a dose-dependent decrease in circulating B cells, and mathematical modeling indicated that a 50% decrease in B cells would be expected with a dose of less than 3 mg of ofatumumab. Individuals who received 3 mg of drug every three months had a 70% reduction in new gadolinium-enhancing lesions, relative to controls. New gadolinium-enhancing lesions in the brain were reduced by more than 90%, relative to controls, in patients who received the three dose regimens of 30 mg of ofatumumab or more.

Over the 24-week treatment phase, six adverse events led to withdrawal from the study (all of these occurring in the treatment arms). The investigators found no differences in the rate of infectious adverse events between the study groups, including placebo treated. Infectious adverse events included nasopharyngitis, urinary tract infection, and respiratory tract infection, but these outcomes were infrequent “and no different from what we have seen in prior anti-CD20–depleting regimens,” said Dr. Bar-Or.

Injection-Related Reactions Were the Most Common Adverse Events
Five individuals had serious adverse events during the first 12 weeks. Another serious adverse event occurred between weeks 12 and 24. The serious adverse events included injection-related reactions, cholelithiasis, cytokine release syndrome, and hypokalemia. Four of these events occurred in patients receiving 60 mg of ofatumumab every month.

“There was no evidence of clinically meaningful changes in laboratory parameters or vital signs,” said Dr. Bar-Or. “There was no evidence of clinically meaningful immunogenicity, including development of human antihuman antibodies, which occurred in only four individuals at low levels and did not appear to impact treatment effect. There were no cases of opportunistic infections, including progressive multifocal lleukoencephalopathy.”

—Erik Greb

DALLAS—A multiple sclerosis (MS) performance test administered by a patient using an iPad-based app is superior to an MS performance test administered by a technician, according to research presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS. The study could prompt changes in the way that data are collected and interpreted for the purposes of clinical trials and disease management, according to Richard Rudick, MD, Vice President of Development Sciences at Biogen Idec in Cambridge, Massachusetts.

The research suggests that unfiltered, accurate patient data could be transferred in real time to the cloud, where it would be available for immediate viewing and for future study. This method of data storage would give clinicians new ways to “collect, display, aggregate, and analyze neurologic performance,” said Dr. Rudick.

iPad Test Distinguished Patients From Controls
Dr. Rudick and his colleagues developed the app-based MS performance test (MSPT) to simulate the technician-based test in all respects. The app-based test comprises a walking speed test, a manual dexterity test, a low-contrast visual acuity test, and a processing speed test. These items approximate the traditional, technician-administered timed 25-foot walk test, the nine-hole peg test, the Sloan low-contrast visual acuity test, and the Symbol Digit Modalities Test.

The cross-sectional validation study matched 49 healthy controls with 51 patients according to age, sex, and education. Roughly three-quarters of the study arm had relapsing MS, and a quarter had the progressive form of the disease.

Participants were tested at a single site with each modality. Tests occurred once in the morning and once in the afternoon. The test and retest results were consistent and correlative, according to Dr. Rudick. “They were highly reliable, whether the technician did it, or the iPad,” he said. Because data for all aspects of each test were comparable, Dr. Rudick concluded that the tests were measuring the same things.

The most important question was how well the app-based test distinguished patients with MS from controls, compared with the technician-based test, according to Dr. Rudick. “In virtually every case, except for the visual [test], the iPad actually does a little bit better than the technician in distinguishing the MS patients from the healthy controls,” he said.

In addition, scores on both tests were highly similar. For the timed 25-foot walk test administered by the technician, the mean score in the MS group was 7, and the mean score for the walking speed test in the MS group was 7.26. In the healthy controls group, the mean score for the technician-given test was 4.24. That group’s mean score for the self-given walking speed test was 4.27.

Technicians Are Still Necessary
Patient-reported outcomes were also consistent with both forms of the tests. In general, however, patient-reported cognitive impairment does not correlate with the results of neurocognitive testing. “What does seem to correlate with patients reporting cognitive impairment is if they are depressed. Then the depression score matches the patient-reported cognitive impairment better than the actual cognitive test score does,” said Dr. Rudick.

Many physician assistants, registered nurses, and physicians may be ready to embrace this app-based technology, but it may not be appropriate for some patients, such as those who walk with difficulty. “You still need a technician to instruct and encourage patients,” said Neil Jouvenat, a physician assistant at the University of Nebraska Medical Center in Omaha. “If the iPad were to instruct a patient to ‘get up now, strap this to your back, and walk 25 feet,’ they won’t because they don’t really think they can. There is a fine line between someone who can walk a certain distance and someone who can’t.” The technician can help in those situations, he added.

The Technology May Aid Clinical Trials
The app holds promise for individuals who would have been excluded from clinical trials in the past, such as patients who live in rural areas. In addition, the collection of normative data from healthy adults will mean that clinical interpretations of MSPT scores will have broader utility in MS patients and groups, and the technology can be adapted to yield additional data such as specific measurements for balance and speed.

Technology such as this has the power to “revolutionize” disease management, particularly if information is collected in a central database that is accessible to any clinician or researcher, said Patricia Coyle, MD, Professor of Psychiatry and Neurology and Director of the MS Comprehensive Care Center at Stony Brook University in New York. “There are only so many MS patients, and we don’t have a good idea of their disease activity. They’re not tracked. No one’s trying to pull that data together,” she said. But having these data “potentially would mean revolutionizing” the field.

—Whitney McKnight

DALLAS—A multiple sclerosis (MS) performance test administered by a patient using an iPad-based app is superior to an MS performance test administered by a technician, according to research presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS. The study could prompt changes in the way that data are collected and interpreted for the purposes of clinical trials and disease management, according to Richard Rudick, MD, Vice President of Development Sciences at Biogen Idec in Cambridge, Massachusetts.

The research suggests that unfiltered, accurate patient data could be transferred in real time to the cloud, where it would be available for immediate viewing and for future study. This method of data storage would give clinicians new ways to “collect, display, aggregate, and analyze neurologic performance,” said Dr. Rudick.

iPad Test Distinguished Patients From Controls
Dr. Rudick and his colleagues developed the app-based MS performance test (MSPT) to simulate the technician-based test in all respects. The app-based test comprises a walking speed test, a manual dexterity test, a low-contrast visual acuity test, and a processing speed test. These items approximate the traditional, technician-administered timed 25-foot walk test, the nine-hole peg test, the Sloan low-contrast visual acuity test, and the Symbol Digit Modalities Test.

The cross-sectional validation study matched 49 healthy controls with 51 patients according to age, sex, and education. Roughly three-quarters of the study arm had relapsing MS, and a quarter had the progressive form of the disease.

Participants were tested at a single site with each modality. Tests occurred once in the morning and once in the afternoon. The test and retest results were consistent and correlative, according to Dr. Rudick. “They were highly reliable, whether the technician did it, or the iPad,” he said. Because data for all aspects of each test were comparable, Dr. Rudick concluded that the tests were measuring the same things.

The most important question was how well the app-based test distinguished patients with MS from controls, compared with the technician-based test, according to Dr. Rudick. “In virtually every case, except for the visual [test], the iPad actually does a little bit better than the technician in distinguishing the MS patients from the healthy controls,” he said.

In addition, scores on both tests were highly similar. For the timed 25-foot walk test administered by the technician, the mean score in the MS group was 7, and the mean score for the walking speed test in the MS group was 7.26. In the healthy controls group, the mean score for the technician-given test was 4.24. That group’s mean score for the self-given walking speed test was 4.27.

Technicians Are Still Necessary
Patient-reported outcomes were also consistent with both forms of the tests. In general, however, patient-reported cognitive impairment does not correlate with the results of neurocognitive testing. “What does seem to correlate with patients reporting cognitive impairment is if they are depressed. Then the depression score matches the patient-reported cognitive impairment better than the actual cognitive test score does,” said Dr. Rudick.

Many physician assistants, registered nurses, and physicians may be ready to embrace this app-based technology, but it may not be appropriate for some patients, such as those who walk with difficulty. “You still need a technician to instruct and encourage patients,” said Neil Jouvenat, a physician assistant at the University of Nebraska Medical Center in Omaha. “If the iPad were to instruct a patient to ‘get up now, strap this to your back, and walk 25 feet,’ they won’t because they don’t really think they can. There is a fine line between someone who can walk a certain distance and someone who can’t.” The technician can help in those situations, he added.

The Technology May Aid Clinical Trials
The app holds promise for individuals who would have been excluded from clinical trials in the past, such as patients who live in rural areas. In addition, the collection of normative data from healthy adults will mean that clinical interpretations of MSPT scores will have broader utility in MS patients and groups, and the technology can be adapted to yield additional data such as specific measurements for balance and speed.

Technology such as this has the power to “revolutionize” disease management, particularly if information is collected in a central database that is accessible to any clinician or researcher, said Patricia Coyle, MD, Professor of Psychiatry and Neurology and Director of the MS Comprehensive Care Center at Stony Brook University in New York. “There are only so many MS patients, and we don’t have a good idea of their disease activity. They’re not tracked. No one’s trying to pull that data together,” she said. But having these data “potentially would mean revolutionizing” the field.

—Whitney McKnight

DALLAS—A multiple sclerosis (MS) performance test administered by a patient using an iPad-based app is superior to an MS performance test administered by a technician, according to research presented at the 2014 Cooperative Meeting of CMSC and ACTRIMS. The study could prompt changes in the way that data are collected and interpreted for the purposes of clinical trials and disease management, according to Richard Rudick, MD, Vice President of Development Sciences at Biogen Idec in Cambridge, Massachusetts.

The research suggests that unfiltered, accurate patient data could be transferred in real time to the cloud, where it would be available for immediate viewing and for future study. This method of data storage would give clinicians new ways to “collect, display, aggregate, and analyze neurologic performance,” said Dr. Rudick.

iPad Test Distinguished Patients From Controls
Dr. Rudick and his colleagues developed the app-based MS performance test (MSPT) to simulate the technician-based test in all respects. The app-based test comprises a walking speed test, a manual dexterity test, a low-contrast visual acuity test, and a processing speed test. These items approximate the traditional, technician-administered timed 25-foot walk test, the nine-hole peg test, the Sloan low-contrast visual acuity test, and the Symbol Digit Modalities Test.

The cross-sectional validation study matched 49 healthy controls with 51 patients according to age, sex, and education. Roughly three-quarters of the study arm had relapsing MS, and a quarter had the progressive form of the disease.

Participants were tested at a single site with each modality. Tests occurred once in the morning and once in the afternoon. The test and retest results were consistent and correlative, according to Dr. Rudick. “They were highly reliable, whether the technician did it, or the iPad,” he said. Because data for all aspects of each test were comparable, Dr. Rudick concluded that the tests were measuring the same things.

The most important question was how well the app-based test distinguished patients with MS from controls, compared with the technician-based test, according to Dr. Rudick. “In virtually every case, except for the visual [test], the iPad actually does a little bit better than the technician in distinguishing the MS patients from the healthy controls,” he said.

In addition, scores on both tests were highly similar. For the timed 25-foot walk test administered by the technician, the mean score in the MS group was 7, and the mean score for the walking speed test in the MS group was 7.26. In the healthy controls group, the mean score for the technician-given test was 4.24. That group’s mean score for the self-given walking speed test was 4.27.

Technicians Are Still Necessary
Patient-reported outcomes were also consistent with both forms of the tests. In general, however, patient-reported cognitive impairment does not correlate with the results of neurocognitive testing. “What does seem to correlate with patients reporting cognitive impairment is if they are depressed. Then the depression score matches the patient-reported cognitive impairment better than the actual cognitive test score does,” said Dr. Rudick.

Many physician assistants, registered nurses, and physicians may be ready to embrace this app-based technology, but it may not be appropriate for some patients, such as those who walk with difficulty. “You still need a technician to instruct and encourage patients,” said Neil Jouvenat, a physician assistant at the University of Nebraska Medical Center in Omaha. “If the iPad were to instruct a patient to ‘get up now, strap this to your back, and walk 25 feet,’ they won’t because they don’t really think they can. There is a fine line between someone who can walk a certain distance and someone who can’t.” The technician can help in those situations, he added.

The Technology May Aid Clinical Trials
The app holds promise for individuals who would have been excluded from clinical trials in the past, such as patients who live in rural areas. In addition, the collection of normative data from healthy adults will mean that clinical interpretations of MSPT scores will have broader utility in MS patients and groups, and the technology can be adapted to yield additional data such as specific measurements for balance and speed.

Technology such as this has the power to “revolutionize” disease management, particularly if information is collected in a central database that is accessible to any clinician or researcher, said Patricia Coyle, MD, Professor of Psychiatry and Neurology and Director of the MS Comprehensive Care Center at Stony Brook University in New York. “There are only so many MS patients, and we don’t have a good idea of their disease activity. They’re not tracked. No one’s trying to pull that data together,” she said. But having these data “potentially would mean revolutionizing” the field.

—Whitney McKnight

DALLAS—Does alemtuzumab have a favorable risk–benefit profile as a treatment for patients with relapsing-remitting multiple sclerosis (MS)? Neurologists who specialize in the disease debated this question at the 2014 Cooperative Meeting of CMSC and ACTRIMS.

Alemtuzumab is approved in Europe, Canada, and Australia for use in patients with MS. The only first-line therapy for refractory MS available in the United States is natalizumab. Among that drug’s drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham virus antibody.

Finding a Balance Between Safety and Efficacy
Many neurologists have raised concerns about alemtuzumab’s safety, but safety is relative, according to Olaf Stüve, MD, PhD, Associate Professor of Neurology and Neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. For any drug, neurologists must identify a good ratio between efficacy and safety that benefits patients more than it hurts them, he added. “I would argue strongly that alemtuzumab has a good efficacy profile that outweighs potential safety issues.” Because natalizumab, which entails its own safety concerns, is the current first-line therapy for patients with refractory disease, “we need another player for patients who don’t respond to disease-modifying therapies,” said Dr. Stüve.

Blinding in an Alemtuzumab Trial Would Be Difficult
The FDA rejected Genzyme’s bid to market alemtuzumab in 2013, citing the lack of double blinding in the Comparison of Alemtuzumab and Rebif Efficacy (CARE) MS I and II trials, as well as concerns about safety.

“It would have been possible to design a double-blinded trial,” said Dr. Stüve. “However, [nearly all] patients are aware which intervention they are receiving, based on any flu-like symptoms. Similarly, an incidence of 90% to 99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent.” Furthermore, because the relapse rate was “fairly consistent in the phase II and phase III programs,” the risk that outcomes were “substantially affected by the trial design,” was reduced, added Dr. Stüve.

Alemtuzumab May Have Long-Lasting Adverse Consequences
“Alemtuzumab is more poison than good,” said Mitchell T. Wallin, MD, Associate Professor of Neurology at Georgetown University in Washington, DC. “My vote is to not approve it. There is some question about how well this drug actually controls disability progression,” he added, referring to the disparate findings of the CARE MS I and II studies. The former trial failed to show that alemtuzumab changed patients’ progression in Expanded Disability Status Scale scores, but the latter trial did show this effect.

Data from the CARE studies, FDA reviews, and an advisory panel meeting of the FDA indicated that alemtuzumab has “good efficacy … in terms of MRI and relapse rates,” said Dr. Wallin. Results of the extended CARE MS trial “seem to show the stabilization of the MRI out to three years,” he added.

But use of the drug often has lethal consequences. Data from the alemtuzumab trials indicate that the drug is associated with a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), said Dr. Wallin. One case of alemtuzumab-related ITP resulted in death.

Approximately 1% of patients studied also had dangerously low platelet counts, which increased their risk for bleeding complications. Reported adverse events, including opportunistic infections, kidney failure, fetal complications, and suicidal ideation, may persuade neurologists that alemtuzumab should not be a first-line therapy. “You give one dose, and the effects probably last at least a year, and some of these effects are seen beyond that,” said Dr. Wallin.

Does Alemtuzumab Compare Favorably to Natalizumab?
Other neurologists believe that the long-lasting effect is precisely what makes alemtuzumab a valuable treatment. “This is a therapy we don’t have to treat patients with indefinitely, or even long term. There is a detectable, dramatic benefit in patients who receive short-term therapy,” said Dr. Stüve. The CARE MS extension data indicated that 20% of patients who had received alemtuzumab received subsequent disease-modifying therapy (DMT) with no increase in adverse events. This result “shows that alemtuzumab could potentially be used as an effective induction therapy up-front and for a limited amount of time, followed by a safe DMT, without added safety concerns,” said Dr. Stüve. “This is something many of us have really been waiting for to treat patients who declare themselves early on as having aggressive disease.”

In addition to ITP, alemtuzumab has been associated with opportunistic infections and various malignancies, including thyroid malignancies. Nevertheless, the extension trial data indicated that these adverse events tend to occur in the third year of treatment, which allows clinicians to anticipate, monitor, and treat these conditions.

When viewed within the entire current treatment landscape, the risks of alemtuzumab are worth the benefits, said Dr. Stüve. “The other player is natalizumab, which has a one in 250 chance of PML, and 20% of those patients die. So I don’t see why I should be squeamish about ITP,” which is treatable. “We should not withhold these kinds of drugs from patients who really need them,” he concluded.

Few Patients May Be Candidates for Alemtuzumab
In theory, Americans could seek treatment with alemtuzumab by traveling to a country where the drug has been approved. Neurologists, however, may discourage patients from traveling for this reason. “Most patients with MS should not be treated with alemtuzumab, so I see little need for anyone to go out of the country to receive it,” said Dennis Bourdette, MD, Director of the MS and Neuroimmunology Center at Oregon Health and Science University in Portland. Patients who chose this option would need extensive follow-up treatment for “autoimmune disease, particularly thyroid disease, platelet abnormalities, kidney dysfunction, and cancer,” he added. Alemtuzumab is a “toxic drug that should be used with great caution and in a small group of patients with active and difficult-to-control disease, perhaps 1% to 2% of cases at most,” concluded Dr. Bourdette.

—Whitney McKnight

DALLAS—Does alemtuzumab have a favorable risk–benefit profile as a treatment for patients with relapsing-remitting multiple sclerosis (MS)? Neurologists who specialize in the disease debated this question at the 2014 Cooperative Meeting of CMSC and ACTRIMS.

Alemtuzumab is approved in Europe, Canada, and Australia for use in patients with MS. The only first-line therapy for refractory MS available in the United States is natalizumab. Among that drug’s drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham virus antibody.

Finding a Balance Between Safety and Efficacy
Many neurologists have raised concerns about alemtuzumab’s safety, but safety is relative, according to Olaf Stüve, MD, PhD, Associate Professor of Neurology and Neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. For any drug, neurologists must identify a good ratio between efficacy and safety that benefits patients more than it hurts them, he added. “I would argue strongly that alemtuzumab has a good efficacy profile that outweighs potential safety issues.” Because natalizumab, which entails its own safety concerns, is the current first-line therapy for patients with refractory disease, “we need another player for patients who don’t respond to disease-modifying therapies,” said Dr. Stüve.

Blinding in an Alemtuzumab Trial Would Be Difficult
The FDA rejected Genzyme’s bid to market alemtuzumab in 2013, citing the lack of double blinding in the Comparison of Alemtuzumab and Rebif Efficacy (CARE) MS I and II trials, as well as concerns about safety.

“It would have been possible to design a double-blinded trial,” said Dr. Stüve. “However, [nearly all] patients are aware which intervention they are receiving, based on any flu-like symptoms. Similarly, an incidence of 90% to 99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent.” Furthermore, because the relapse rate was “fairly consistent in the phase II and phase III programs,” the risk that outcomes were “substantially affected by the trial design,” was reduced, added Dr. Stüve.

Alemtuzumab May Have Long-Lasting Adverse Consequences
“Alemtuzumab is more poison than good,” said Mitchell T. Wallin, MD, Associate Professor of Neurology at Georgetown University in Washington, DC. “My vote is to not approve it. There is some question about how well this drug actually controls disability progression,” he added, referring to the disparate findings of the CARE MS I and II studies. The former trial failed to show that alemtuzumab changed patients’ progression in Expanded Disability Status Scale scores, but the latter trial did show this effect.

Data from the CARE studies, FDA reviews, and an advisory panel meeting of the FDA indicated that alemtuzumab has “good efficacy … in terms of MRI and relapse rates,” said Dr. Wallin. Results of the extended CARE MS trial “seem to show the stabilization of the MRI out to three years,” he added.

But use of the drug often has lethal consequences. Data from the alemtuzumab trials indicate that the drug is associated with a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), said Dr. Wallin. One case of alemtuzumab-related ITP resulted in death.

Approximately 1% of patients studied also had dangerously low platelet counts, which increased their risk for bleeding complications. Reported adverse events, including opportunistic infections, kidney failure, fetal complications, and suicidal ideation, may persuade neurologists that alemtuzumab should not be a first-line therapy. “You give one dose, and the effects probably last at least a year, and some of these effects are seen beyond that,” said Dr. Wallin.

Does Alemtuzumab Compare Favorably to Natalizumab?
Other neurologists believe that the long-lasting effect is precisely what makes alemtuzumab a valuable treatment. “This is a therapy we don’t have to treat patients with indefinitely, or even long term. There is a detectable, dramatic benefit in patients who receive short-term therapy,” said Dr. Stüve. The CARE MS extension data indicated that 20% of patients who had received alemtuzumab received subsequent disease-modifying therapy (DMT) with no increase in adverse events. This result “shows that alemtuzumab could potentially be used as an effective induction therapy up-front and for a limited amount of time, followed by a safe DMT, without added safety concerns,” said Dr. Stüve. “This is something many of us have really been waiting for to treat patients who declare themselves early on as having aggressive disease.”

In addition to ITP, alemtuzumab has been associated with opportunistic infections and various malignancies, including thyroid malignancies. Nevertheless, the extension trial data indicated that these adverse events tend to occur in the third year of treatment, which allows clinicians to anticipate, monitor, and treat these conditions.

When viewed within the entire current treatment landscape, the risks of alemtuzumab are worth the benefits, said Dr. Stüve. “The other player is natalizumab, which has a one in 250 chance of PML, and 20% of those patients die. So I don’t see why I should be squeamish about ITP,” which is treatable. “We should not withhold these kinds of drugs from patients who really need them,” he concluded.

Few Patients May Be Candidates for Alemtuzumab
In theory, Americans could seek treatment with alemtuzumab by traveling to a country where the drug has been approved. Neurologists, however, may discourage patients from traveling for this reason. “Most patients with MS should not be treated with alemtuzumab, so I see little need for anyone to go out of the country to receive it,” said Dennis Bourdette, MD, Director of the MS and Neuroimmunology Center at Oregon Health and Science University in Portland. Patients who chose this option would need extensive follow-up treatment for “autoimmune disease, particularly thyroid disease, platelet abnormalities, kidney dysfunction, and cancer,” he added. Alemtuzumab is a “toxic drug that should be used with great caution and in a small group of patients with active and difficult-to-control disease, perhaps 1% to 2% of cases at most,” concluded Dr. Bourdette.

—Whitney McKnight

DALLAS—Does alemtuzumab have a favorable risk–benefit profile as a treatment for patients with relapsing-remitting multiple sclerosis (MS)? Neurologists who specialize in the disease debated this question at the 2014 Cooperative Meeting of CMSC and ACTRIMS.

Alemtuzumab is approved in Europe, Canada, and Australia for use in patients with MS. The only first-line therapy for refractory MS available in the United States is natalizumab. Among that drug’s drawbacks is the increased risk of progressive multifocal leukoencephalopathy (PML) in patients who test positive for the John Cunningham virus antibody.

Finding a Balance Between Safety and Efficacy
Many neurologists have raised concerns about alemtuzumab’s safety, but safety is relative, according to Olaf Stüve, MD, PhD, Associate Professor of Neurology and Neurotherapeutics at the University of Texas Southwestern Medical Center in Dallas. For any drug, neurologists must identify a good ratio between efficacy and safety that benefits patients more than it hurts them, he added. “I would argue strongly that alemtuzumab has a good efficacy profile that outweighs potential safety issues.” Because natalizumab, which entails its own safety concerns, is the current first-line therapy for patients with refractory disease, “we need another player for patients who don’t respond to disease-modifying therapies,” said Dr. Stüve.

Blinding in an Alemtuzumab Trial Would Be Difficult
The FDA rejected Genzyme’s bid to market alemtuzumab in 2013, citing the lack of double blinding in the Comparison of Alemtuzumab and Rebif Efficacy (CARE) MS I and II trials, as well as concerns about safety.

“It would have been possible to design a double-blinded trial,” said Dr. Stüve. “However, [nearly all] patients are aware which intervention they are receiving, based on any flu-like symptoms. Similarly, an incidence of 90% to 99% infusion-related reactions under alemtuzumab would likely make it impossible to blind for that agent.” Furthermore, because the relapse rate was “fairly consistent in the phase II and phase III programs,” the risk that outcomes were “substantially affected by the trial design,” was reduced, added Dr. Stüve.

Alemtuzumab May Have Long-Lasting Adverse Consequences
“Alemtuzumab is more poison than good,” said Mitchell T. Wallin, MD, Associate Professor of Neurology at Georgetown University in Washington, DC. “My vote is to not approve it. There is some question about how well this drug actually controls disability progression,” he added, referring to the disparate findings of the CARE MS I and II studies. The former trial failed to show that alemtuzumab changed patients’ progression in Expanded Disability Status Scale scores, but the latter trial did show this effect.

Data from the CARE studies, FDA reviews, and an advisory panel meeting of the FDA indicated that alemtuzumab has “good efficacy … in terms of MRI and relapse rates,” said Dr. Wallin. Results of the extended CARE MS trial “seem to show the stabilization of the MRI out to three years,” he added.

But use of the drug often has lethal consequences. Data from the alemtuzumab trials indicate that the drug is associated with a greater than 2% occurrence of a distinctive form of immune thrombocytopenia (ITP), said Dr. Wallin. One case of alemtuzumab-related ITP resulted in death.

Approximately 1% of patients studied also had dangerously low platelet counts, which increased their risk for bleeding complications. Reported adverse events, including opportunistic infections, kidney failure, fetal complications, and suicidal ideation, may persuade neurologists that alemtuzumab should not be a first-line therapy. “You give one dose, and the effects probably last at least a year, and some of these effects are seen beyond that,” said Dr. Wallin.

Does Alemtuzumab Compare Favorably to Natalizumab?
Other neurologists believe that the long-lasting effect is precisely what makes alemtuzumab a valuable treatment. “This is a therapy we don’t have to treat patients with indefinitely, or even long term. There is a detectable, dramatic benefit in patients who receive short-term therapy,” said Dr. Stüve. The CARE MS extension data indicated that 20% of patients who had received alemtuzumab received subsequent disease-modifying therapy (DMT) with no increase in adverse events. This result “shows that alemtuzumab could potentially be used as an effective induction therapy up-front and for a limited amount of time, followed by a safe DMT, without added safety concerns,” said Dr. Stüve. “This is something many of us have really been waiting for to treat patients who declare themselves early on as having aggressive disease.”

In addition to ITP, alemtuzumab has been associated with opportunistic infections and various malignancies, including thyroid malignancies. Nevertheless, the extension trial data indicated that these adverse events tend to occur in the third year of treatment, which allows clinicians to anticipate, monitor, and treat these conditions.

When viewed within the entire current treatment landscape, the risks of alemtuzumab are worth the benefits, said Dr. Stüve. “The other player is natalizumab, which has a one in 250 chance of PML, and 20% of those patients die. So I don’t see why I should be squeamish about ITP,” which is treatable. “We should not withhold these kinds of drugs from patients who really need them,” he concluded.

Few Patients May Be Candidates for Alemtuzumab
In theory, Americans could seek treatment with alemtuzumab by traveling to a country where the drug has been approved. Neurologists, however, may discourage patients from traveling for this reason. “Most patients with MS should not be treated with alemtuzumab, so I see little need for anyone to go out of the country to receive it,” said Dennis Bourdette, MD, Director of the MS and Neuroimmunology Center at Oregon Health and Science University in Portland. Patients who chose this option would need extensive follow-up treatment for “autoimmune disease, particularly thyroid disease, platelet abnormalities, kidney dysfunction, and cancer,” he added. Alemtuzumab is a “toxic drug that should be used with great caution and in a small group of patients with active and difficult-to-control disease, perhaps 1% to 2% of cases at most,” concluded Dr. Bourdette.

—Whitney McKnight

DALLAS—Patients with multiple sclerosis (MS) who have a higher BMI and weight in early adulthood have a younger age of MS symptom onset and diagnosis, according to research presented at the 2014 Cooperative Meeting of the CMSC and ACTRIMS.

Katelyn S. Kavak, from the Jacobs MS Center in Buffalo, New York, and colleagues based their findings on a study of 237 women who were registered with the New York State MS Consortium, had completed a questionnaire about reproductive events, and were treated at the investigators’ MS care center. All study participants were asked to recall their weight at the time of their first menstruation and at age 25.

The researchers calculated BMI for age 25 but not for the time of first menstruation, because “height measures in adolescence could not reliably be deduced.” The investigators used regression analysis to examine the association between weight or BMI as a continuous measure and age at MS onset and diagnosis. In addition, the study authors compared people who were overweight with those who were not overweight, defining those who were overweight as having a BMI greater than or equal to 25 and those who were not overweight as having a BMI less than 25.

“Weight of subjects at their first menstruation was significantly related to younger age at [MS symptom] onset and diagnosis,” reported the researchers. “These results were also found at age 25 for onset and diagnosis. Subjects with higher BMI at age 25 were younger at onset and diagnosis.” Further analysis that compared overweight and nonoverweight persons found that those who were overweight at age 25 had a “significantly earlier” age at MS symptom onset and diagnosis.

“Future research should investigate whether there is a causal link between body weight and MS, as there may be underlying genetic or environmental factors, such as vitamin D deficiency, that could influence the results,” the researchers concluded.

—Colby Stong

A Personalized Management Plan of Fingolimod Titration May Benefit Some Patients With MS
Long-term data demonstrating the success of interferon titration suggest that a similar strategy could be effective for a select group of patients who have difficulty tolerating the initial recommended 0.5-mg daily fingolimod dose. Data suggest that there may be a role for fingolimod 0.25 mg/day; however, the optimal recommended therapeutic dose of 0.5 mg/day is achievable for many patients if side effects and titration are managed efficiently and effectively.

A major Australian tertiary teaching hospital with a large multiple sclerosis (MS) clinic anticipated that patients starting on fingolimod and experiencing poor drug tolerability would request, or simply decide on their own, to cease their medication. Historical experience with interferon prompted discussions with the neurologist and MS nursing staff. Through consultation in relation to dosing alternatives, an opportunity to explore individualized oral drug titration was identified. Select patients whose quality of life was being disrupted by unwanted side effects were offered a titration and monitoring opportunity. The goal of the “go slow” approach was to achieve the full recommended daily dose regimen and establish confidence with a nonexistent or minimal acceptable side effect profile.

Susanne Baker and Meena Sharma from the MS Clinic at Liverpool Hospital in Sydney, Australia, in collaboration with neurologists, endeavored to manage side effects and titrate the fingolimod dose according to side effects experienced. Patients who chose to withdraw from fingolimod treatment were given the option of a personalized management plan. No clinical assessment tool was used to grade the severity of the adverse events, and all supportive care was given based on the patients’ self-report of discomfort. The program offered regular monitoring and side effect management for lymphopenia, gastrointestinal disturbance, headache, and a feeling of being generally unwell. Ongoing consultation with the neurologist by the MS nursing staff was maintained along with fingolimod dose adjustments. Supportive medication included, but was not limited to, paracetamol, ibuprofen, ranitidine, metoclopramide, and loperamide.

In total, 209 patients were treated with fingolimod at the MS clinic at Liverpool Hospital, and 51 (24.4%) significant adverse events (eg, lymphopenia, herpes zoster, malignancy, headache, ophthalmologic symptoms, gastrointestinal disturbance, and a feeling of being generally unwell) were reported. From this patient group, 24 (47%) were offered a side effect management and drug titration plan. Sixteen patients (66.7%) chose to participate in the proposed plan. A total of 10 participants were able to achieve the full dose and remain on treatment, two (12.5%) patients discontinued treatment due to poor tolerance, and four (25%) patients remained on drug titration. No relapses were observed or reported during the titration period.

—Glenn S. Williams

Vitamin D Deficiency Predicts Long-Term Disease Activity in Patients Taking Interferon Beta-1b
Correcting vitamin D deficiency early in the course of treatment with interferon beta-1b is likely to improve the outcome for patients with multiple sclerosis (MS), according to data presented.

“The results of this study support the importance of identifying and correcting 25(OH)D insufficiency early in the course of MS,” said Alberto Ascherio, MD, DrPH, and colleagues. “The effects are likely additive to therapy with interferon beta-1b without decreasing its tolerability.”

Dr. Ascherio, from the Harvard School of Public Health in Boston, and colleagues sought to examine the predictive effect of serum 25(OH)D levels on disease activity and progression in patients with clinically isolated syndrome starting interferon beta-1b therapy. They also examined the effect of serum 25(OH)D levels on the occurrence of flu-like symptoms, a common side-effect of interferon beta-1b.

Drawing their study cohort from the BEtaferon/BEtaseron in Newly Emerging MS for Initial Treatment (BENEFIT) study, the researchers randomized patients with clinically isolated syndrome and two or more clinically silent brain MRI lesions to 250 µg of interferon beta-1b (early treatment) or placebo (late treatment) subcutaneously every other day. Serum 25(OH)D concentration measurements were taken at baseline and at six, 12, and 24 months. Cox proportional hazard models or generalized mixed effects models were used to relate season-adjusted 25(OH)D concentrations to clinical and MRI outcomes up to five years. Occurrence of flu-like symptoms in the early treatment group with high or low serum 25(OH)D levels were compared by χ² test.

Data from 216 patients in the early treatment group and 118 patients in the delayed treatment group were analyzed. When analyzed as a continuous variable, increases in 25(OH)D led to a lower probability of conversion to McDonald MS, with a trend toward lower probability of conversion to clinically definite MS. Increases in 25(OH)D also led to lower rates of newly active lesions, relapses, annual percent change in T2 volume, and annual percent change in brain volume.

Dichotomous 25(OH)D levels were strongly and inversely associated with probability of conversion to clinically definite MS, cumulative number of new lesions on MRI, percent change in T2 volume, and percent change in brain volume. Occurrence of flu-like symptoms did not differ between patients in the early treatment group with high or low serum 25(OH)D levels at months 6, 12, and 24.

Dr. Ascherio and colleagues concluded that among patients who started interferon beta-1b treatment right after clinically isolated syndrome, incremental increases of 25(OH)D levels were associated with reduction of long-term MS disease activity and severity. “These results also suggest that early treatment with interferon beta-1b has an additive effect with 25(OH)D to reduce disease severity and progression on both clinical and imaging outcomes.”

Further research would be needed, the researchers said, to determine whether these results apply to patients with different MS subtypes or those treated with drugs other than interferon beta-1b.

—Glenn S. Williams

Late-Onset MS Largely Involves Relapsing-Remitting Course
Eighty-two percent of patients who present with late-onset multiple sclerosis (MS) have a relapsing-remitting course of their disease, and the others have a progressive illness, researchers reported.

Claudia Chaves, MD, and colleagues retrospectively reviewed the database from the Lahey Hospital and Medical Center’s MS Center in Lexington, Massachusetts, and selected patients with new-onset MS at age 50 and older. The investigators sought to determine the clinical characteristics and imaging features among patients with late-onset MS.

Fifty patients who presented to the clinic had late-onset MS, which was 7% of all patients with MS, according to Dr. Chaves. Forty-one patients (30 women; mean age, 55) had a relapsing-remitting course, and nine patients (seven women; mean age, 53.6) had a progressive illness. Gait problems were present in 80% of patients with relapsing-remitting MS and in all patients with progressive disease. Patients with progressive illness were significantly more likely to have motor deficits and a higher Expanded Disability Status Scale (EDSS) score, compared with those with relapsing-remitting MS.

Patients with progressive illness had higher odds of cognitive impairment and more difficulties with coordination, though the rate was not statistically significant. Patients with relapsing-remitting MS had 2.2 times the odds of having sensory abnormalities. “No statistically significant difference was found for MRI measures between the two groups, including the presence of supra- and infratentorial lesions, spinal cord involvement, contrast enhancement, and cerebral atrophy,” noted the investigators.

However, the odds of infratentorial and spinal cord involvement were higher in those patients with relapsing-remitting MS and those with progressive illness, respectively.” Ninety percent of patients with relapsing-remitting MS had been treated with a disease-modifying agent, and 78% of those with progressive illness were treated with a disease-modifying agent.

“Gait difficulties were common in both groups, with motor deficits and higher EDSS score significantly more common in patients with progressive disease,” the researchers concluded. “The MRI findings and clinical evolution were not significantly different between the two groups over the time period studied.”

—Colby Stong

Is Daycare Exposure a Protective Factor Against Neuromyelitis Optica in Children?
Early exposure to other young children may be a protective factor against the development of neuromyelitis optica, suggesting that viral infections may contribute to disease risk modification, researchers reported.

Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco, Pediatric MS Center, and colleagues sought to determine whether environmental factors known to modify the risk for multiple sclerosis (MS) were associated with the risk for neuromyelitis optica in children. The researchers used a chemoluminescence assay to measure serum 25(OH) vitamin D levels, and Epstein-Barr virus, cytomegalovirus, herpes simplex virus-1, and herpes simplex virus-2 antibody responses were determined by ELISA. The investigators also used multivariate logistic regression models to determine risk factor associations with neuromyelitis optica, including adjustments for age at sampling, sex, race, and ethnicity.

Analysis was based on 36 children with neuromyelitis optica, 491 with MS, and 224 healthy controls. Dr. Graves and colleagues found that daycare (odds ratio [OR], 0.33) and breastfeeding (OR, 0.41) were associated with lower odds of having neuromyelitis optica, compared with healthy children. “C-section tended to be associated with a twofold higher odds of neuromyelitis optica,” stated Dr. Graves. “Parental smoking was not meaningfully associated with neuromyelitis optica risk.”

A total of 34 children with neuromyelitis optica, 189 with MS, and 94 controls had serotyping. The investigators found that Epstein-Barr virus exposure “tended to be associated” with lower odds of having neuromyelitis optica, compared with children with MS. Exposure to herpes simplex virus-1 and being DRB1*15-positive were also associated with lower odds of having neuromyelitis optica.

“Unlike MS, pediatric neuromyelitis optica does not appear to be associated with exposures to common herpes viruses,” the investigators concluded.

—Colby Stong

Attitudes Toward Exercise Correlate With Perceived Autonomy and Pain Among Patients With MS
Scores on Guy’s Neurological Disability Scale (GNDS) correlate well with walking distance and presence of pain and spasticity among patients with multiple sclerosis (MS), according to researchers. In addition, the Multidimensional Outcome Expectations for Exercise Scale (MOEES) questionnaire three subscales appear valid, and self-evaluative scale scores correlate with pain scores, as well as with a physical measure. Lead author Samuel M. Bierner, MD, and colleagues said that their early analysis revealed interesting relationships between patients’ perceived autonomy and daily pain scores. Dr. Bierner is affiliated with the Department of Physical Medicine and Rehabilitation at the University of Texas Southwestern Medical Center in Dallas.

Dr. Bierner and colleagues conducted a prospective cohort study designed to assess the relationship between attitudes toward exercise and autonomy and physical measures of upper and lower body strength and exercise performed. They reported the initial results of the cohort at the time of entry into the study.

Patients from an academic MS center completed two physical measures: grip strength dynamometry and the two-minute walk test (2MWT). They also completed the GNDS, the Impact on Participation and Autonomy Questionnaire (IPA), and the MOEES, previously validated in the ambulatory MS population. A medical history relevant to MS was elicited. In the second part of the study (not reported here), the subjects completed an exercise diary for two weeks.

The initial study of 46 subjects showed a mean GNDS score of 10.7 for males and 12.1 for females, and these scores were not statistically different. Bivariate correlation analyses showed a significant relationship between GNDS and 2MWT, as well as GNDS and presence of pain or spasticity.

The IPA subscales—Autonomy Indoors scale, Family Role scale, and Autonomy Outdoors scale—showed significant correlations with average daily pain rating.

The MOEES scale data evaluated by principal components analysis showed excellent agreement with published three-subscale factor model. The Self-Evaluative subscale showed significant correlation with average daily pain rating.

Grip dynamometry results were 30.9 kg for the left hand and 32.1 kg for the right hand. Regression model showed that right-hand grip was predicted by MOEES Self-Evaluative subscale score, fatigue, and gender.

According to Dr. Bierner and colleagues, their initial study showed a relatively healthy sample, with GNDS disability scores lower than other published studies. Average grip strength was within normal limits for age and gender. The 2MWT was negatively correlated with GNDS total score and all IPA subscales. As expected, subjects who were able to walk greater distances had less perceived disability and greater autonomy and participation in their daily activities.

Subjects’ pain ratings correlated with multiple questionnaire scores, including the GNDS total score (reflecting perceived MS disability), the MOEES self-evaluative subscale, and all IPA subscales except work/education. Pain appears to affect one’s self-evaluation, sense of disability, autonomy, and participation in daily activities.

According to the researchers, the three MOEES subscales (physical, social, and self-evaluative outcome expectations) appear valid. Principal component analysis of the MOEES responses from the 46 subjects revealed three factors that matched 13 of the 15 (86.7%) original questions used in the study validation. Question 9 (ie, “Exercise will aid in weight control”) and Question 13 (ie, “Exercise will increase my mental alertness”) were the two mismatches. The researchers noted that mean values from each subscale nearly matched those values published in the original MOEES validation paper.

—Glenn S. Williams

Functional Electrical Stimulation Cycling May Be Beneficial in Moderate to Severe MS
Functional electrical stimulation (FES) cycling may be an effective exercise option in people who have moderate to severe multiple sclerosis (MS), reported Deborah Backus, PhD, and colleagues.

The study included 16 people with MS who had an Expanded Disability Status Scale score of greater than 6.5. Subjects trained two to three times per week for about one month (ie, in a total of 12 sessions) on the RT-300 FES cycle, and the intensity of FES was adjusted for each participant’s comfort level. “The goal was to cycle at 40 to 50 rpm for 30 minutes, either actively or with electrical stimulation for assistance,” noted Dr. Backus, who is the Director of MS Research at the Eula C. and Andrew C. Carlos MS Rehabilitation and Wellness Program at the Shepherd Center in Atlanta.

The investigators analyzed data collected immediately before and after the four-week training period using the MS Quality of Life Inventory (MSQLI) subscales, Modified Ashworth Scale (MAS, spasticity), and manual muscle test (MMT, strength). The study authors also collected data from each training session to monitor subjects’ progress on the cycle and any status changes.

Fourteen participants (six females) completed the training. The researchers found that all persons maintained or increased the amount of time that they could cycle, and seven increased the resistance against which they cycled.

“The most important finding is that there were no adverse events and no increase in any MS-related symptoms,” said Dr. Backus. “Participants demonstrated a significant increase in one measure of cognitive processing speed and a significant decrease in fatigue. There was no significant change in the other subscales of the MSQLI. There was neither a significant increase nor a decrease in MAS and MMT scores.”

The investigators also found that the type of MS and use of antispasticity medications, disease-modifying therapies, or dalfampridine or 4-aminopyridine “did not appear to influence the response to training.

“Further study is required to examine the parameters of FES cycling that are most effective for people with different constellations of MS symptoms and to fully explore the potential benefits for optimizing function and improving health in people with moderate to severe MS,” Dr. Backus concluded.

—Colby Stong

Clinical Characteristics Predictive of High Costs Among Patients With MS
Baseline use of corticosteroids and documentation of other brain MRI results may be significantly associated with higher costs for patients with multiple sclerosis (MS), according to data presented.

“This study provides insight into factors associated with high-cost MS patients and may help to prospectively identify potential high-cost MS patients who may benefit from cost-effective proactive clinical management,” the researchers said. “Additionally, while most patients have documentation of brain MRI in their medical records, many of the additional clinical characteristics needed to assess disease severity are not documented in the medical record.”

Debra F. Eisenberg, MS, PhD, and colleagues sought to assess patient demographics, clinical characteristics, medication use, and resource use among patients with MS stratified as low, medium, and high cost through administrative claims review and patient medical record review. For their observational, retrospective cohort study, the researchers used data drawn from the HealthCore Integrated Research Database (HIRD), which includes medical and pharmacy claims data.

Patients age 18 or older newly diagnosed with MS during the period from January 1, 2007, to April 30, 2011, were identified in the database. Annualized MS-related cost was computed, and patients were classified into high-, medium-, and low-cost strata. A total of 400 patients with a confirmed diagnosis of MS and documentation of brain MRI were selected for medical record review. Bivariate analyses and multivariate logistic regression models were used to identify factors associated with high-cost patients.

Among the 400 patient medical records abstracted, 84, 132, and 184 patients were in the low-, medium-, and high-cost groups, respectively. Patients included in the analysis had a mean age of 41 at diagnosis, and 70% were female. Nearly all (97%) of the patients had brain MRI results documented in their medical records. Of the 389 patients with MRI results, 31.7% of the low-, 53.6% of the medium-, and 35.2% of the high-cost patients had active brain lesions. Common symptoms reported were numbness (63%), fatigue (59%), and pain (59%). Relapsing-remitting disease was documented in 14% of the low-, 40% of the medium-, and 33% of the high-cost patients. Approximately 50% of the patients had gait impairment, ranging from 38% of the low-, 44% of the medium-, and 64% of the high-cost patients. Other brain MRI results not related to T2 imaging, active lesions, demyelination, black holes, and brain atrophy were seen to a greater extent among high-cost patients.

In addition, high-cost patients were more likely to use antidepressants (31.5%), corticosteroids (43.5%), narcotics (38.6%), and stimulants (6.5%). High-cost patients also were more likely to have electrocardiogram (36.4%) and spinal tap (20.1%) procedures.

Lead author Dr. Eisenberg is affiliated with HealthCore, a company headquartered in Wilmington, Delaware.

—Glenn S. Williams

DALLAS—Patients with multiple sclerosis (MS) who have a higher BMI and weight in early adulthood have a younger age of MS symptom onset and diagnosis, according to research presented at the 2014 Cooperative Meeting of the CMSC and ACTRIMS.

Katelyn S. Kavak, from the Jacobs MS Center in Buffalo, New York, and colleagues based their findings on a study of 237 women who were registered with the New York State MS Consortium, had completed a questionnaire about reproductive events, and were treated at the investigators’ MS care center. All study participants were asked to recall their weight at the time of their first menstruation and at age 25.

The researchers calculated BMI for age 25 but not for the time of first menstruation, because “height measures in adolescence could not reliably be deduced.” The investigators used regression analysis to examine the association between weight or BMI as a continuous measure and age at MS onset and diagnosis. In addition, the study authors compared people who were overweight with those who were not overweight, defining those who were overweight as having a BMI greater than or equal to 25 and those who were not overweight as having a BMI less than 25.

“Weight of subjects at their first menstruation was significantly related to younger age at [MS symptom] onset and diagnosis,” reported the researchers. “These results were also found at age 25 for onset and diagnosis. Subjects with higher BMI at age 25 were younger at onset and diagnosis.” Further analysis that compared overweight and nonoverweight persons found that those who were overweight at age 25 had a “significantly earlier” age at MS symptom onset and diagnosis.

“Future research should investigate whether there is a causal link between body weight and MS, as there may be underlying genetic or environmental factors, such as vitamin D deficiency, that could influence the results,” the researchers concluded.

—Colby Stong

A Personalized Management Plan of Fingolimod Titration May Benefit Some Patients With MS
Long-term data demonstrating the success of interferon titration suggest that a similar strategy could be effective for a select group of patients who have difficulty tolerating the initial recommended 0.5-mg daily fingolimod dose. Data suggest that there may be a role for fingolimod 0.25 mg/day; however, the optimal recommended therapeutic dose of 0.5 mg/day is achievable for many patients if side effects and titration are managed efficiently and effectively.

A major Australian tertiary teaching hospital with a large multiple sclerosis (MS) clinic anticipated that patients starting on fingolimod and experiencing poor drug tolerability would request, or simply decide on their own, to cease their medication. Historical experience with interferon prompted discussions with the neurologist and MS nursing staff. Through consultation in relation to dosing alternatives, an opportunity to explore individualized oral drug titration was identified. Select patients whose quality of life was being disrupted by unwanted side effects were offered a titration and monitoring opportunity. The goal of the “go slow” approach was to achieve the full recommended daily dose regimen and establish confidence with a nonexistent or minimal acceptable side effect profile.

Susanne Baker and Meena Sharma from the MS Clinic at Liverpool Hospital in Sydney, Australia, in collaboration with neurologists, endeavored to manage side effects and titrate the fingolimod dose according to side effects experienced. Patients who chose to withdraw from fingolimod treatment were given the option of a personalized management plan. No clinical assessment tool was used to grade the severity of the adverse events, and all supportive care was given based on the patients’ self-report of discomfort. The program offered regular monitoring and side effect management for lymphopenia, gastrointestinal disturbance, headache, and a feeling of being generally unwell. Ongoing consultation with the neurologist by the MS nursing staff was maintained along with fingolimod dose adjustments. Supportive medication included, but was not limited to, paracetamol, ibuprofen, ranitidine, metoclopramide, and loperamide.

In total, 209 patients were treated with fingolimod at the MS clinic at Liverpool Hospital, and 51 (24.4%) significant adverse events (eg, lymphopenia, herpes zoster, malignancy, headache, ophthalmologic symptoms, gastrointestinal disturbance, and a feeling of being generally unwell) were reported. From this patient group, 24 (47%) were offered a side effect management and drug titration plan. Sixteen patients (66.7%) chose to participate in the proposed plan. A total of 10 participants were able to achieve the full dose and remain on treatment, two (12.5%) patients discontinued treatment due to poor tolerance, and four (25%) patients remained on drug titration. No relapses were observed or reported during the titration period.

—Glenn S. Williams

Vitamin D Deficiency Predicts Long-Term Disease Activity in Patients Taking Interferon Beta-1b
Correcting vitamin D deficiency early in the course of treatment with interferon beta-1b is likely to improve the outcome for patients with multiple sclerosis (MS), according to data presented.

“The results of this study support the importance of identifying and correcting 25(OH)D insufficiency early in the course of MS,” said Alberto Ascherio, MD, DrPH, and colleagues. “The effects are likely additive to therapy with interferon beta-1b without decreasing its tolerability.”

Dr. Ascherio, from the Harvard School of Public Health in Boston, and colleagues sought to examine the predictive effect of serum 25(OH)D levels on disease activity and progression in patients with clinically isolated syndrome starting interferon beta-1b therapy. They also examined the effect of serum 25(OH)D levels on the occurrence of flu-like symptoms, a common side-effect of interferon beta-1b.

Drawing their study cohort from the BEtaferon/BEtaseron in Newly Emerging MS for Initial Treatment (BENEFIT) study, the researchers randomized patients with clinically isolated syndrome and two or more clinically silent brain MRI lesions to 250 µg of interferon beta-1b (early treatment) or placebo (late treatment) subcutaneously every other day. Serum 25(OH)D concentration measurements were taken at baseline and at six, 12, and 24 months. Cox proportional hazard models or generalized mixed effects models were used to relate season-adjusted 25(OH)D concentrations to clinical and MRI outcomes up to five years. Occurrence of flu-like symptoms in the early treatment group with high or low serum 25(OH)D levels were compared by χ² test.

Data from 216 patients in the early treatment group and 118 patients in the delayed treatment group were analyzed. When analyzed as a continuous variable, increases in 25(OH)D led to a lower probability of conversion to McDonald MS, with a trend toward lower probability of conversion to clinically definite MS. Increases in 25(OH)D also led to lower rates of newly active lesions, relapses, annual percent change in T2 volume, and annual percent change in brain volume.

Dichotomous 25(OH)D levels were strongly and inversely associated with probability of conversion to clinically definite MS, cumulative number of new lesions on MRI, percent change in T2 volume, and percent change in brain volume. Occurrence of flu-like symptoms did not differ between patients in the early treatment group with high or low serum 25(OH)D levels at months 6, 12, and 24.

Dr. Ascherio and colleagues concluded that among patients who started interferon beta-1b treatment right after clinically isolated syndrome, incremental increases of 25(OH)D levels were associated with reduction of long-term MS disease activity and severity. “These results also suggest that early treatment with interferon beta-1b has an additive effect with 25(OH)D to reduce disease severity and progression on both clinical and imaging outcomes.”

Further research would be needed, the researchers said, to determine whether these results apply to patients with different MS subtypes or those treated with drugs other than interferon beta-1b.

—Glenn S. Williams

Late-Onset MS Largely Involves Relapsing-Remitting Course
Eighty-two percent of patients who present with late-onset multiple sclerosis (MS) have a relapsing-remitting course of their disease, and the others have a progressive illness, researchers reported.

Claudia Chaves, MD, and colleagues retrospectively reviewed the database from the Lahey Hospital and Medical Center’s MS Center in Lexington, Massachusetts, and selected patients with new-onset MS at age 50 and older. The investigators sought to determine the clinical characteristics and imaging features among patients with late-onset MS.

Fifty patients who presented to the clinic had late-onset MS, which was 7% of all patients with MS, according to Dr. Chaves. Forty-one patients (30 women; mean age, 55) had a relapsing-remitting course, and nine patients (seven women; mean age, 53.6) had a progressive illness. Gait problems were present in 80% of patients with relapsing-remitting MS and in all patients with progressive disease. Patients with progressive illness were significantly more likely to have motor deficits and a higher Expanded Disability Status Scale (EDSS) score, compared with those with relapsing-remitting MS.

Patients with progressive illness had higher odds of cognitive impairment and more difficulties with coordination, though the rate was not statistically significant. Patients with relapsing-remitting MS had 2.2 times the odds of having sensory abnormalities. “No statistically significant difference was found for MRI measures between the two groups, including the presence of supra- and infratentorial lesions, spinal cord involvement, contrast enhancement, and cerebral atrophy,” noted the investigators.

However, the odds of infratentorial and spinal cord involvement were higher in those patients with relapsing-remitting MS and those with progressive illness, respectively.” Ninety percent of patients with relapsing-remitting MS had been treated with a disease-modifying agent, and 78% of those with progressive illness were treated with a disease-modifying agent.

“Gait difficulties were common in both groups, with motor deficits and higher EDSS score significantly more common in patients with progressive disease,” the researchers concluded. “The MRI findings and clinical evolution were not significantly different between the two groups over the time period studied.”

—Colby Stong

Is Daycare Exposure a Protective Factor Against Neuromyelitis Optica in Children?
Early exposure to other young children may be a protective factor against the development of neuromyelitis optica, suggesting that viral infections may contribute to disease risk modification, researchers reported.

Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco, Pediatric MS Center, and colleagues sought to determine whether environmental factors known to modify the risk for multiple sclerosis (MS) were associated with the risk for neuromyelitis optica in children. The researchers used a chemoluminescence assay to measure serum 25(OH) vitamin D levels, and Epstein-Barr virus, cytomegalovirus, herpes simplex virus-1, and herpes simplex virus-2 antibody responses were determined by ELISA. The investigators also used multivariate logistic regression models to determine risk factor associations with neuromyelitis optica, including adjustments for age at sampling, sex, race, and ethnicity.

Analysis was based on 36 children with neuromyelitis optica, 491 with MS, and 224 healthy controls. Dr. Graves and colleagues found that daycare (odds ratio [OR], 0.33) and breastfeeding (OR, 0.41) were associated with lower odds of having neuromyelitis optica, compared with healthy children. “C-section tended to be associated with a twofold higher odds of neuromyelitis optica,” stated Dr. Graves. “Parental smoking was not meaningfully associated with neuromyelitis optica risk.”

A total of 34 children with neuromyelitis optica, 189 with MS, and 94 controls had serotyping. The investigators found that Epstein-Barr virus exposure “tended to be associated” with lower odds of having neuromyelitis optica, compared with children with MS. Exposure to herpes simplex virus-1 and being DRB1*15-positive were also associated with lower odds of having neuromyelitis optica.

“Unlike MS, pediatric neuromyelitis optica does not appear to be associated with exposures to common herpes viruses,” the investigators concluded.

—Colby Stong

Attitudes Toward Exercise Correlate With Perceived Autonomy and Pain Among Patients With MS
Scores on Guy’s Neurological Disability Scale (GNDS) correlate well with walking distance and presence of pain and spasticity among patients with multiple sclerosis (MS), according to researchers. In addition, the Multidimensional Outcome Expectations for Exercise Scale (MOEES) questionnaire three subscales appear valid, and self-evaluative scale scores correlate with pain scores, as well as with a physical measure. Lead author Samuel M. Bierner, MD, and colleagues said that their early analysis revealed interesting relationships between patients’ perceived autonomy and daily pain scores. Dr. Bierner is affiliated with the Department of Physical Medicine and Rehabilitation at the University of Texas Southwestern Medical Center in Dallas.

Dr. Bierner and colleagues conducted a prospective cohort study designed to assess the relationship between attitudes toward exercise and autonomy and physical measures of upper and lower body strength and exercise performed. They reported the initial results of the cohort at the time of entry into the study.

Patients from an academic MS center completed two physical measures: grip strength dynamometry and the two-minute walk test (2MWT). They also completed the GNDS, the Impact on Participation and Autonomy Questionnaire (IPA), and the MOEES, previously validated in the ambulatory MS population. A medical history relevant to MS was elicited. In the second part of the study (not reported here), the subjects completed an exercise diary for two weeks.

The initial study of 46 subjects showed a mean GNDS score of 10.7 for males and 12.1 for females, and these scores were not statistically different. Bivariate correlation analyses showed a significant relationship between GNDS and 2MWT, as well as GNDS and presence of pain or spasticity.

The IPA subscales—Autonomy Indoors scale, Family Role scale, and Autonomy Outdoors scale—showed significant correlations with average daily pain rating.

The MOEES scale data evaluated by principal components analysis showed excellent agreement with published three-subscale factor model. The Self-Evaluative subscale showed significant correlation with average daily pain rating.

Grip dynamometry results were 30.9 kg for the left hand and 32.1 kg for the right hand. Regression model showed that right-hand grip was predicted by MOEES Self-Evaluative subscale score, fatigue, and gender.

According to Dr. Bierner and colleagues, their initial study showed a relatively healthy sample, with GNDS disability scores lower than other published studies. Average grip strength was within normal limits for age and gender. The 2MWT was negatively correlated with GNDS total score and all IPA subscales. As expected, subjects who were able to walk greater distances had less perceived disability and greater autonomy and participation in their daily activities.

Subjects’ pain ratings correlated with multiple questionnaire scores, including the GNDS total score (reflecting perceived MS disability), the MOEES self-evaluative subscale, and all IPA subscales except work/education. Pain appears to affect one’s self-evaluation, sense of disability, autonomy, and participation in daily activities.

According to the researchers, the three MOEES subscales (physical, social, and self-evaluative outcome expectations) appear valid. Principal component analysis of the MOEES responses from the 46 subjects revealed three factors that matched 13 of the 15 (86.7%) original questions used in the study validation. Question 9 (ie, “Exercise will aid in weight control”) and Question 13 (ie, “Exercise will increase my mental alertness”) were the two mismatches. The researchers noted that mean values from each subscale nearly matched those values published in the original MOEES validation paper.

—Glenn S. Williams

Functional Electrical Stimulation Cycling May Be Beneficial in Moderate to Severe MS
Functional electrical stimulation (FES) cycling may be an effective exercise option in people who have moderate to severe multiple sclerosis (MS), reported Deborah Backus, PhD, and colleagues.

The study included 16 people with MS who had an Expanded Disability Status Scale score of greater than 6.5. Subjects trained two to three times per week for about one month (ie, in a total of 12 sessions) on the RT-300 FES cycle, and the intensity of FES was adjusted for each participant’s comfort level. “The goal was to cycle at 40 to 50 rpm for 30 minutes, either actively or with electrical stimulation for assistance,” noted Dr. Backus, who is the Director of MS Research at the Eula C. and Andrew C. Carlos MS Rehabilitation and Wellness Program at the Shepherd Center in Atlanta.

The investigators analyzed data collected immediately before and after the four-week training period using the MS Quality of Life Inventory (MSQLI) subscales, Modified Ashworth Scale (MAS, spasticity), and manual muscle test (MMT, strength). The study authors also collected data from each training session to monitor subjects’ progress on the cycle and any status changes.

Fourteen participants (six females) completed the training. The researchers found that all persons maintained or increased the amount of time that they could cycle, and seven increased the resistance against which they cycled.

“The most important finding is that there were no adverse events and no increase in any MS-related symptoms,” said Dr. Backus. “Participants demonstrated a significant increase in one measure of cognitive processing speed and a significant decrease in fatigue. There was no significant change in the other subscales of the MSQLI. There was neither a significant increase nor a decrease in MAS and MMT scores.”

The investigators also found that the type of MS and use of antispasticity medications, disease-modifying therapies, or dalfampridine or 4-aminopyridine “did not appear to influence the response to training.

“Further study is required to examine the parameters of FES cycling that are most effective for people with different constellations of MS symptoms and to fully explore the potential benefits for optimizing function and improving health in people with moderate to severe MS,” Dr. Backus concluded.

—Colby Stong

Clinical Characteristics Predictive of High Costs Among Patients With MS
Baseline use of corticosteroids and documentation of other brain MRI results may be significantly associated with higher costs for patients with multiple sclerosis (MS), according to data presented.

“This study provides insight into factors associated with high-cost MS patients and may help to prospectively identify potential high-cost MS patients who may benefit from cost-effective proactive clinical management,” the researchers said. “Additionally, while most patients have documentation of brain MRI in their medical records, many of the additional clinical characteristics needed to assess disease severity are not documented in the medical record.”

Debra F. Eisenberg, MS, PhD, and colleagues sought to assess patient demographics, clinical characteristics, medication use, and resource use among patients with MS stratified as low, medium, and high cost through administrative claims review and patient medical record review. For their observational, retrospective cohort study, the researchers used data drawn from the HealthCore Integrated Research Database (HIRD), which includes medical and pharmacy claims data.

Patients age 18 or older newly diagnosed with MS during the period from January 1, 2007, to April 30, 2011, were identified in the database. Annualized MS-related cost was computed, and patients were classified into high-, medium-, and low-cost strata. A total of 400 patients with a confirmed diagnosis of MS and documentation of brain MRI were selected for medical record review. Bivariate analyses and multivariate logistic regression models were used to identify factors associated with high-cost patients.

Among the 400 patient medical records abstracted, 84, 132, and 184 patients were in the low-, medium-, and high-cost groups, respectively. Patients included in the analysis had a mean age of 41 at diagnosis, and 70% were female. Nearly all (97%) of the patients had brain MRI results documented in their medical records. Of the 389 patients with MRI results, 31.7% of the low-, 53.6% of the medium-, and 35.2% of the high-cost patients had active brain lesions. Common symptoms reported were numbness (63%), fatigue (59%), and pain (59%). Relapsing-remitting disease was documented in 14% of the low-, 40% of the medium-, and 33% of the high-cost patients. Approximately 50% of the patients had gait impairment, ranging from 38% of the low-, 44% of the medium-, and 64% of the high-cost patients. Other brain MRI results not related to T2 imaging, active lesions, demyelination, black holes, and brain atrophy were seen to a greater extent among high-cost patients.

In addition, high-cost patients were more likely to use antidepressants (31.5%), corticosteroids (43.5%), narcotics (38.6%), and stimulants (6.5%). High-cost patients also were more likely to have electrocardiogram (36.4%) and spinal tap (20.1%) procedures.

Lead author Dr. Eisenberg is affiliated with HealthCore, a company headquartered in Wilmington, Delaware.

—Glenn S. Williams

DALLAS—Patients with multiple sclerosis (MS) who have a higher BMI and weight in early adulthood have a younger age of MS symptom onset and diagnosis, according to research presented at the 2014 Cooperative Meeting of the CMSC and ACTRIMS.

Katelyn S. Kavak, from the Jacobs MS Center in Buffalo, New York, and colleagues based their findings on a study of 237 women who were registered with the New York State MS Consortium, had completed a questionnaire about reproductive events, and were treated at the investigators’ MS care center. All study participants were asked to recall their weight at the time of their first menstruation and at age 25.

The researchers calculated BMI for age 25 but not for the time of first menstruation, because “height measures in adolescence could not reliably be deduced.” The investigators used regression analysis to examine the association between weight or BMI as a continuous measure and age at MS onset and diagnosis. In addition, the study authors compared people who were overweight with those who were not overweight, defining those who were overweight as having a BMI greater than or equal to 25 and those who were not overweight as having a BMI less than 25.

“Weight of subjects at their first menstruation was significantly related to younger age at [MS symptom] onset and diagnosis,” reported the researchers. “These results were also found at age 25 for onset and diagnosis. Subjects with higher BMI at age 25 were younger at onset and diagnosis.” Further analysis that compared overweight and nonoverweight persons found that those who were overweight at age 25 had a “significantly earlier” age at MS symptom onset and diagnosis.

“Future research should investigate whether there is a causal link between body weight and MS, as there may be underlying genetic or environmental factors, such as vitamin D deficiency, that could influence the results,” the researchers concluded.

—Colby Stong

A Personalized Management Plan of Fingolimod Titration May Benefit Some Patients With MS
Long-term data demonstrating the success of interferon titration suggest that a similar strategy could be effective for a select group of patients who have difficulty tolerating the initial recommended 0.5-mg daily fingolimod dose. Data suggest that there may be a role for fingolimod 0.25 mg/day; however, the optimal recommended therapeutic dose of 0.5 mg/day is achievable for many patients if side effects and titration are managed efficiently and effectively.

A major Australian tertiary teaching hospital with a large multiple sclerosis (MS) clinic anticipated that patients starting on fingolimod and experiencing poor drug tolerability would request, or simply decide on their own, to cease their medication. Historical experience with interferon prompted discussions with the neurologist and MS nursing staff. Through consultation in relation to dosing alternatives, an opportunity to explore individualized oral drug titration was identified. Select patients whose quality of life was being disrupted by unwanted side effects were offered a titration and monitoring opportunity. The goal of the “go slow” approach was to achieve the full recommended daily dose regimen and establish confidence with a nonexistent or minimal acceptable side effect profile.

Susanne Baker and Meena Sharma from the MS Clinic at Liverpool Hospital in Sydney, Australia, in collaboration with neurologists, endeavored to manage side effects and titrate the fingolimod dose according to side effects experienced. Patients who chose to withdraw from fingolimod treatment were given the option of a personalized management plan. No clinical assessment tool was used to grade the severity of the adverse events, and all supportive care was given based on the patients’ self-report of discomfort. The program offered regular monitoring and side effect management for lymphopenia, gastrointestinal disturbance, headache, and a feeling of being generally unwell. Ongoing consultation with the neurologist by the MS nursing staff was maintained along with fingolimod dose adjustments. Supportive medication included, but was not limited to, paracetamol, ibuprofen, ranitidine, metoclopramide, and loperamide.

In total, 209 patients were treated with fingolimod at the MS clinic at Liverpool Hospital, and 51 (24.4%) significant adverse events (eg, lymphopenia, herpes zoster, malignancy, headache, ophthalmologic symptoms, gastrointestinal disturbance, and a feeling of being generally unwell) were reported. From this patient group, 24 (47%) were offered a side effect management and drug titration plan. Sixteen patients (66.7%) chose to participate in the proposed plan. A total of 10 participants were able to achieve the full dose and remain on treatment, two (12.5%) patients discontinued treatment due to poor tolerance, and four (25%) patients remained on drug titration. No relapses were observed or reported during the titration period.

—Glenn S. Williams

Vitamin D Deficiency Predicts Long-Term Disease Activity in Patients Taking Interferon Beta-1b
Correcting vitamin D deficiency early in the course of treatment with interferon beta-1b is likely to improve the outcome for patients with multiple sclerosis (MS), according to data presented.

“The results of this study support the importance of identifying and correcting 25(OH)D insufficiency early in the course of MS,” said Alberto Ascherio, MD, DrPH, and colleagues. “The effects are likely additive to therapy with interferon beta-1b without decreasing its tolerability.”

Dr. Ascherio, from the Harvard School of Public Health in Boston, and colleagues sought to examine the predictive effect of serum 25(OH)D levels on disease activity and progression in patients with clinically isolated syndrome starting interferon beta-1b therapy. They also examined the effect of serum 25(OH)D levels on the occurrence of flu-like symptoms, a common side-effect of interferon beta-1b.

Drawing their study cohort from the BEtaferon/BEtaseron in Newly Emerging MS for Initial Treatment (BENEFIT) study, the researchers randomized patients with clinically isolated syndrome and two or more clinically silent brain MRI lesions to 250 µg of interferon beta-1b (early treatment) or placebo (late treatment) subcutaneously every other day. Serum 25(OH)D concentration measurements were taken at baseline and at six, 12, and 24 months. Cox proportional hazard models or generalized mixed effects models were used to relate season-adjusted 25(OH)D concentrations to clinical and MRI outcomes up to five years. Occurrence of flu-like symptoms in the early treatment group with high or low serum 25(OH)D levels were compared by χ² test.

Data from 216 patients in the early treatment group and 118 patients in the delayed treatment group were analyzed. When analyzed as a continuous variable, increases in 25(OH)D led to a lower probability of conversion to McDonald MS, with a trend toward lower probability of conversion to clinically definite MS. Increases in 25(OH)D also led to lower rates of newly active lesions, relapses, annual percent change in T2 volume, and annual percent change in brain volume.

Dichotomous 25(OH)D levels were strongly and inversely associated with probability of conversion to clinically definite MS, cumulative number of new lesions on MRI, percent change in T2 volume, and percent change in brain volume. Occurrence of flu-like symptoms did not differ between patients in the early treatment group with high or low serum 25(OH)D levels at months 6, 12, and 24.

Dr. Ascherio and colleagues concluded that among patients who started interferon beta-1b treatment right after clinically isolated syndrome, incremental increases of 25(OH)D levels were associated with reduction of long-term MS disease activity and severity. “These results also suggest that early treatment with interferon beta-1b has an additive effect with 25(OH)D to reduce disease severity and progression on both clinical and imaging outcomes.”

Further research would be needed, the researchers said, to determine whether these results apply to patients with different MS subtypes or those treated with drugs other than interferon beta-1b.

—Glenn S. Williams

Late-Onset MS Largely Involves Relapsing-Remitting Course
Eighty-two percent of patients who present with late-onset multiple sclerosis (MS) have a relapsing-remitting course of their disease, and the others have a progressive illness, researchers reported.

Claudia Chaves, MD, and colleagues retrospectively reviewed the database from the Lahey Hospital and Medical Center’s MS Center in Lexington, Massachusetts, and selected patients with new-onset MS at age 50 and older. The investigators sought to determine the clinical characteristics and imaging features among patients with late-onset MS.

Fifty patients who presented to the clinic had late-onset MS, which was 7% of all patients with MS, according to Dr. Chaves. Forty-one patients (30 women; mean age, 55) had a relapsing-remitting course, and nine patients (seven women; mean age, 53.6) had a progressive illness. Gait problems were present in 80% of patients with relapsing-remitting MS and in all patients with progressive disease. Patients with progressive illness were significantly more likely to have motor deficits and a higher Expanded Disability Status Scale (EDSS) score, compared with those with relapsing-remitting MS.

Patients with progressive illness had higher odds of cognitive impairment and more difficulties with coordination, though the rate was not statistically significant. Patients with relapsing-remitting MS had 2.2 times the odds of having sensory abnormalities. “No statistically significant difference was found for MRI measures between the two groups, including the presence of supra- and infratentorial lesions, spinal cord involvement, contrast enhancement, and cerebral atrophy,” noted the investigators.

However, the odds of infratentorial and spinal cord involvement were higher in those patients with relapsing-remitting MS and those with progressive illness, respectively.” Ninety percent of patients with relapsing-remitting MS had been treated with a disease-modifying agent, and 78% of those with progressive illness were treated with a disease-modifying agent.

“Gait difficulties were common in both groups, with motor deficits and higher EDSS score significantly more common in patients with progressive disease,” the researchers concluded. “The MRI findings and clinical evolution were not significantly different between the two groups over the time period studied.”

—Colby Stong

Is Daycare Exposure a Protective Factor Against Neuromyelitis Optica in Children?
Early exposure to other young children may be a protective factor against the development of neuromyelitis optica, suggesting that viral infections may contribute to disease risk modification, researchers reported.

Jennifer Graves, MD, PhD, Assistant Professor of Neurology at the University of California, San Francisco, Pediatric MS Center, and colleagues sought to determine whether environmental factors known to modify the risk for multiple sclerosis (MS) were associated with the risk for neuromyelitis optica in children. The researchers used a chemoluminescence assay to measure serum 25(OH) vitamin D levels, and Epstein-Barr virus, cytomegalovirus, herpes simplex virus-1, and herpes simplex virus-2 antibody responses were determined by ELISA. The investigators also used multivariate logistic regression models to determine risk factor associations with neuromyelitis optica, including adjustments for age at sampling, sex, race, and ethnicity.

Analysis was based on 36 children with neuromyelitis optica, 491 with MS, and 224 healthy controls. Dr. Graves and colleagues found that daycare (odds ratio [OR], 0.33) and breastfeeding (OR, 0.41) were associated with lower odds of having neuromyelitis optica, compared with healthy children. “C-section tended to be associated with a twofold higher odds of neuromyelitis optica,” stated Dr. Graves. “Parental smoking was not meaningfully associated with neuromyelitis optica risk.”

A total of 34 children with neuromyelitis optica, 189 with MS, and 94 controls had serotyping. The investigators found that Epstein-Barr virus exposure “tended to be associated” with lower odds of having neuromyelitis optica, compared with children with MS. Exposure to herpes simplex virus-1 and being DRB1*15-positive were also associated with lower odds of having neuromyelitis optica.

“Unlike MS, pediatric neuromyelitis optica does not appear to be associated with exposures to common herpes viruses,” the investigators concluded.

—Colby Stong

Attitudes Toward Exercise Correlate With Perceived Autonomy and Pain Among Patients With MS
Scores on Guy’s Neurological Disability Scale (GNDS) correlate well with walking distance and presence of pain and spasticity among patients with multiple sclerosis (MS), according to researchers. In addition, the Multidimensional Outcome Expectations for Exercise Scale (MOEES) questionnaire three subscales appear valid, and self-evaluative scale scores correlate with pain scores, as well as with a physical measure. Lead author Samuel M. Bierner, MD, and colleagues said that their early analysis revealed interesting relationships between patients’ perceived autonomy and daily pain scores. Dr. Bierner is affiliated with the Department of Physical Medicine and Rehabilitation at the University of Texas Southwestern Medical Center in Dallas.

Dr. Bierner and colleagues conducted a prospective cohort study designed to assess the relationship between attitudes toward exercise and autonomy and physical measures of upper and lower body strength and exercise performed. They reported the initial results of the cohort at the time of entry into the study.

Patients from an academic MS center completed two physical measures: grip strength dynamometry and the two-minute walk test (2MWT). They also completed the GNDS, the Impact on Participation and Autonomy Questionnaire (IPA), and the MOEES, previously validated in the ambulatory MS population. A medical history relevant to MS was elicited. In the second part of the study (not reported here), the subjects completed an exercise diary for two weeks.

The initial study of 46 subjects showed a mean GNDS score of 10.7 for males and 12.1 for females, and these scores were not statistically different. Bivariate correlation analyses showed a significant relationship between GNDS and 2MWT, as well as GNDS and presence of pain or spasticity.

The IPA subscales—Autonomy Indoors scale, Family Role scale, and Autonomy Outdoors scale—showed significant correlations with average daily pain rating.

The MOEES scale data evaluated by principal components analysis showed excellent agreement with published three-subscale factor model. The Self-Evaluative subscale showed significant correlation with average daily pain rating.

Grip dynamometry results were 30.9 kg for the left hand and 32.1 kg for the right hand. Regression model showed that right-hand grip was predicted by MOEES Self-Evaluative subscale score, fatigue, and gender.

According to Dr. Bierner and colleagues, their initial study showed a relatively healthy sample, with GNDS disability scores lower than other published studies. Average grip strength was within normal limits for age and gender. The 2MWT was negatively correlated with GNDS total score and all IPA subscales. As expected, subjects who were able to walk greater distances had less perceived disability and greater autonomy and participation in their daily activities.

Subjects’ pain ratings correlated with multiple questionnaire scores, including the GNDS total score (reflecting perceived MS disability), the MOEES self-evaluative subscale, and all IPA subscales except work/education. Pain appears to affect one’s self-evaluation, sense of disability, autonomy, and participation in daily activities.

According to the researchers, the three MOEES subscales (physical, social, and self-evaluative outcome expectations) appear valid. Principal component analysis of the MOEES responses from the 46 subjects revealed three factors that matched 13 of the 15 (86.7%) original questions used in the study validation. Question 9 (ie, “Exercise will aid in weight control”) and Question 13 (ie, “Exercise will increase my mental alertness”) were the two mismatches. The researchers noted that mean values from each subscale nearly matched those values published in the original MOEES validation paper.

—Glenn S. Williams

Functional Electrical Stimulation Cycling May Be Beneficial in Moderate to Severe MS
Functional electrical stimulation (FES) cycling may be an effective exercise option in people who have moderate to severe multiple sclerosis (MS), reported Deborah Backus, PhD, and colleagues.

The study included 16 people with MS who had an Expanded Disability Status Scale score of greater than 6.5. Subjects trained two to three times per week for about one month (ie, in a total of 12 sessions) on the RT-300 FES cycle, and the intensity of FES was adjusted for each participant’s comfort level. “The goal was to cycle at 40 to 50 rpm for 30 minutes, either actively or with electrical stimulation for assistance,” noted Dr. Backus, who is the Director of MS Research at the Eula C. and Andrew C. Carlos MS Rehabilitation and Wellness Program at the Shepherd Center in Atlanta.

The investigators analyzed data collected immediately before and after the four-week training period using the MS Quality of Life Inventory (MSQLI) subscales, Modified Ashworth Scale (MAS, spasticity), and manual muscle test (MMT, strength). The study authors also collected data from each training session to monitor subjects’ progress on the cycle and any status changes.

Fourteen participants (six females) completed the training. The researchers found that all persons maintained or increased the amount of time that they could cycle, and seven increased the resistance against which they cycled.

“The most important finding is that there were no adverse events and no increase in any MS-related symptoms,” said Dr. Backus. “Participants demonstrated a significant increase in one measure of cognitive processing speed and a significant decrease in fatigue. There was no significant change in the other subscales of the MSQLI. There was neither a significant increase nor a decrease in MAS and MMT scores.”

The investigators also found that the type of MS and use of antispasticity medications, disease-modifying therapies, or dalfampridine or 4-aminopyridine “did not appear to influence the response to training.

“Further study is required to examine the parameters of FES cycling that are most effective for people with different constellations of MS symptoms and to fully explore the potential benefits for optimizing function and improving health in people with moderate to severe MS,” Dr. Backus concluded.

—Colby Stong

Clinical Characteristics Predictive of High Costs Among Patients With MS
Baseline use of corticosteroids and documentation of other brain MRI results may be significantly associated with higher costs for patients with multiple sclerosis (MS), according to data presented.

“This study provides insight into factors associated with high-cost MS patients and may help to prospectively identify potential high-cost MS patients who may benefit from cost-effective proactive clinical management,” the researchers said. “Additionally, while most patients have documentation of brain MRI in their medical records, many of the additional clinical characteristics needed to assess disease severity are not documented in the medical record.”

Debra F. Eisenberg, MS, PhD, and colleagues sought to assess patient demographics, clinical characteristics, medication use, and resource use among patients with MS stratified as low, medium, and high cost through administrative claims review and patient medical record review. For their observational, retrospective cohort study, the researchers used data drawn from the HealthCore Integrated Research Database (HIRD), which includes medical and pharmacy claims data.

Patients age 18 or older newly diagnosed with MS during the period from January 1, 2007, to April 30, 2011, were identified in the database. Annualized MS-related cost was computed, and patients were classified into high-, medium-, and low-cost strata. A total of 400 patients with a confirmed diagnosis of MS and documentation of brain MRI were selected for medical record review. Bivariate analyses and multivariate logistic regression models were used to identify factors associated with high-cost patients.

Among the 400 patient medical records abstracted, 84, 132, and 184 patients were in the low-, medium-, and high-cost groups, respectively. Patients included in the analysis had a mean age of 41 at diagnosis, and 70% were female. Nearly all (97%) of the patients had brain MRI results documented in their medical records. Of the 389 patients with MRI results, 31.7% of the low-, 53.6% of the medium-, and 35.2% of the high-cost patients had active brain lesions. Common symptoms reported were numbness (63%), fatigue (59%), and pain (59%). Relapsing-remitting disease was documented in 14% of the low-, 40% of the medium-, and 33% of the high-cost patients. Approximately 50% of the patients had gait impairment, ranging from 38% of the low-, 44% of the medium-, and 64% of the high-cost patients. Other brain MRI results not related to T2 imaging, active lesions, demyelination, black holes, and brain atrophy were seen to a greater extent among high-cost patients.

In addition, high-cost patients were more likely to use antidepressants (31.5%), corticosteroids (43.5%), narcotics (38.6%), and stimulants (6.5%). High-cost patients also were more likely to have electrocardiogram (36.4%) and spinal tap (20.1%) procedures.

Lead author Dr. Eisenberg is affiliated with HealthCore, a company headquartered in Wilmington, Delaware.

—Glenn S. Williams

Patients with multiple sclerosis (MS) and larger maximal lifetime brain growth (MLBG) had less decline in cognitive efficiency, and patients with greater intellectual enrichment had a lower risk for decline in cognitive efficiency and memory over 4.5 years, according to a study published May 20 in Neurology.

James F. Sumowski, PhD, Senior Research Scientist of Neuropsychology and Neuroscience at the Kessler Foundation Research Center in West Orange, New Jersey, and colleagues evaluated cognitive efficiency and memory in 40 patients with MS at baseline and at a 4.5-year follow-up. The researchers used MRI to quantify disease progression and percentage change in T2 lesion volume.

Dr. Sumowski’s group found that the patients declined in cognitive efficiency and memory. MLBG moderated decline in cognitive efficiency, and larger MLBG protected against this decline. However, MLBG did not moderate memory decline. Also, intellectual enrichment moderated decline in cognitive efficiency and memory, and greater intellectual enrichment protected against decline. In addition, MS disease progression was more negatively associated with change in cognitive efficiency and memory among patients with lower versus higher MLBG and intellectual enrichment.

“Clinically, it is difficult to predict which patients with MS are at greatest risk of cognitive decline because it is difficult to accurately predict MS disease progression for any given patient,” stated the researchers. “MLBG and intellectual enrichment are important factors to consider when trying to predict cognitive decline in patients with MS, because patients with lower MLBG and/or lesser intellectual enrichment are at greatest risk of cognitive decline. These at-risk patients can be targeted for early-intervention cognitive rehabilitation, which may help prevent/delay the onset of functional impairment.

“Higher cardiorespiratory fitness may help preserve brain volume and cognitive efficiency, and preliminary data show that aerobic exercise training may result in improved memory, increased hippocampal volume, and increased hippocampal functional connectivity in patients with MS,” the investigators commented. “Finally, patients with MS should also be encouraged to engage in intellectual enrichment (eg, reading, hobbies, etc), because previous research and the current findings suggest that greater intellectual enrichment protects against cognitive decline.”

—Colby Stong

Patients with multiple sclerosis (MS) and larger maximal lifetime brain growth (MLBG) had less decline in cognitive efficiency, and patients with greater intellectual enrichment had a lower risk for decline in cognitive efficiency and memory over 4.5 years, according to a study published May 20 in Neurology.

James F. Sumowski, PhD, Senior Research Scientist of Neuropsychology and Neuroscience at the Kessler Foundation Research Center in West Orange, New Jersey, and colleagues evaluated cognitive efficiency and memory in 40 patients with MS at baseline and at a 4.5-year follow-up. The researchers used MRI to quantify disease progression and percentage change in T2 lesion volume.

Dr. Sumowski’s group found that the patients declined in cognitive efficiency and memory. MLBG moderated decline in cognitive efficiency, and larger MLBG protected against this decline. However, MLBG did not moderate memory decline. Also, intellectual enrichment moderated decline in cognitive efficiency and memory, and greater intellectual enrichment protected against decline. In addition, MS disease progression was more negatively associated with change in cognitive efficiency and memory among patients with lower versus higher MLBG and intellectual enrichment.

“Clinically, it is difficult to predict which patients with MS are at greatest risk of cognitive decline because it is difficult to accurately predict MS disease progression for any given patient,” stated the researchers. “MLBG and intellectual enrichment are important factors to consider when trying to predict cognitive decline in patients with MS, because patients with lower MLBG and/or lesser intellectual enrichment are at greatest risk of cognitive decline. These at-risk patients can be targeted for early-intervention cognitive rehabilitation, which may help prevent/delay the onset of functional impairment.

“Higher cardiorespiratory fitness may help preserve brain volume and cognitive efficiency, and preliminary data show that aerobic exercise training may result in improved memory, increased hippocampal volume, and increased hippocampal functional connectivity in patients with MS,” the investigators commented. “Finally, patients with MS should also be encouraged to engage in intellectual enrichment (eg, reading, hobbies, etc), because previous research and the current findings suggest that greater intellectual enrichment protects against cognitive decline.”

—Colby Stong

Patients with multiple sclerosis (MS) and larger maximal lifetime brain growth (MLBG) had less decline in cognitive efficiency, and patients with greater intellectual enrichment had a lower risk for decline in cognitive efficiency and memory over 4.5 years, according to a study published May 20 in Neurology.

James F. Sumowski, PhD, Senior Research Scientist of Neuropsychology and Neuroscience at the Kessler Foundation Research Center in West Orange, New Jersey, and colleagues evaluated cognitive efficiency and memory in 40 patients with MS at baseline and at a 4.5-year follow-up. The researchers used MRI to quantify disease progression and percentage change in T2 lesion volume.

Dr. Sumowski’s group found that the patients declined in cognitive efficiency and memory. MLBG moderated decline in cognitive efficiency, and larger MLBG protected against this decline. However, MLBG did not moderate memory decline. Also, intellectual enrichment moderated decline in cognitive efficiency and memory, and greater intellectual enrichment protected against decline. In addition, MS disease progression was more negatively associated with change in cognitive efficiency and memory among patients with lower versus higher MLBG and intellectual enrichment.

“Clinically, it is difficult to predict which patients with MS are at greatest risk of cognitive decline because it is difficult to accurately predict MS disease progression for any given patient,” stated the researchers. “MLBG and intellectual enrichment are important factors to consider when trying to predict cognitive decline in patients with MS, because patients with lower MLBG and/or lesser intellectual enrichment are at greatest risk of cognitive decline. These at-risk patients can be targeted for early-intervention cognitive rehabilitation, which may help prevent/delay the onset of functional impairment.

“Higher cardiorespiratory fitness may help preserve brain volume and cognitive efficiency, and preliminary data show that aerobic exercise training may result in improved memory, increased hippocampal volume, and increased hippocampal functional connectivity in patients with MS,” the investigators commented. “Finally, patients with MS should also be encouraged to engage in intellectual enrichment (eg, reading, hobbies, etc), because previous research and the current findings suggest that greater intellectual enrichment protects against cognitive decline.”

—Colby Stong

Patients with multiple sclerosis (MS) who smoke marijuana regularly have more cognitive deficits than patients with MS who do not smoke marijuana, according to research published May 27 in Neurology. Marijuana use may be associated with impairments in information processing speed, visual memory, and working memory among these individuals.

In a cross-sectional study, cannabis users had more diffuse cerebral activation during a test of working memory, compared with nonusers. The cannabis users also had increased activation in parietal and anterior cingulate brain regions implicated in working memory, relative to nonusers.

But investigators found no differences in brain structure between the study groups, and this finding is consistent with the results of cannabis imaging studies in healthy subjects.

Subjects Underwent Imaging and Neuropsychologic Tests
Bennis Pavisian, research assistant at Sunnybrook Hospital in Toronto, and colleagues recruited 39 patients (ages 18 to 60) with a confirmed diagnosis of MS for their study. They enrolled 20 participants who regularly used cannabis and whose urine tested positive for cannabis metabolites. The investigators asked participants not to use cannabis for 12 hours before the trial. Nineteen patients with MS who had never used cannabis were matched to the other participants using demographic and disease-related variables.

All participants underwent the Brief Repeatable Battery of Neuropsychological Tests in MS, which includes measures of verbal and visual memory, information processing speed, and attention.

The researchers assessed patients’ premorbid IQ with the Wechsler Test of Adult Reading, measured anxiety and depression with the Hospital Anxiety and Depression Scale, and gauged fatigue with the modified Fatigue Impact Scale.

All subjects also underwent the n-Back test of working memory, which had been modified to avoid verbal responses.

The investigators performed fMRI while the participants were taking the n-Back test. They also collected resting-state fMRI and structural MRI data, including lesion and normal-appearing brain tissue volumes and diffusion tensor imaging metrics.

Brain Activation Was More Diffuse Among Marijuana Users
Patients who used cannabis performed worse on the two-second Paced Auditory Serial Addition Test and the 10/36 Spatial Recall Test. Both groups had similar scores on the tests of fatigue, anxiety, and depression. Global cognitive impairment did not correlate with frequency of cannabis use or urine concentration of metabolites.

The investigators found no statistically significant between-group differences on fMRI for the 0- and 1-Back tests. The cannabis group gave fewer correct responses on the 2-Back trial, compared with controls, but had no difference in reaction times.

The researchers found no significant differences in resting state network activation between the two patient groups. During the n-Back test, all patients activated prefrontal, anterior cingulate, and posterior parietal circuits. Several secondary regions activated as well on the 0-Back and 2-Back tests, and the activation pattern was more diffuse in the cannabis group.

Parietal and anterior cingulate activations were only present in the cannabis group for both tasks, according to the investigators. Frontal activation was more prominent in the cannabis group across tasks.

—Erik Greb

Patients with multiple sclerosis (MS) who smoke marijuana regularly have more cognitive deficits than patients with MS who do not smoke marijuana, according to research published May 27 in Neurology. Marijuana use may be associated with impairments in information processing speed, visual memory, and working memory among these individuals.

In a cross-sectional study, cannabis users had more diffuse cerebral activation during a test of working memory, compared with nonusers. The cannabis users also had increased activation in parietal and anterior cingulate brain regions implicated in working memory, relative to nonusers.

But investigators found no differences in brain structure between the study groups, and this finding is consistent with the results of cannabis imaging studies in healthy subjects.

Subjects Underwent Imaging and Neuropsychologic Tests
Bennis Pavisian, research assistant at Sunnybrook Hospital in Toronto, and colleagues recruited 39 patients (ages 18 to 60) with a confirmed diagnosis of MS for their study. They enrolled 20 participants who regularly used cannabis and whose urine tested positive for cannabis metabolites. The investigators asked participants not to use cannabis for 12 hours before the trial. Nineteen patients with MS who had never used cannabis were matched to the other participants using demographic and disease-related variables.

All participants underwent the Brief Repeatable Battery of Neuropsychological Tests in MS, which includes measures of verbal and visual memory, information processing speed, and attention.

The researchers assessed patients’ premorbid IQ with the Wechsler Test of Adult Reading, measured anxiety and depression with the Hospital Anxiety and Depression Scale, and gauged fatigue with the modified Fatigue Impact Scale.

All subjects also underwent the n-Back test of working memory, which had been modified to avoid verbal responses.

The investigators performed fMRI while the participants were taking the n-Back test. They also collected resting-state fMRI and structural MRI data, including lesion and normal-appearing brain tissue volumes and diffusion tensor imaging metrics.

Brain Activation Was More Diffuse Among Marijuana Users
Patients who used cannabis performed worse on the two-second Paced Auditory Serial Addition Test and the 10/36 Spatial Recall Test. Both groups had similar scores on the tests of fatigue, anxiety, and depression. Global cognitive impairment did not correlate with frequency of cannabis use or urine concentration of metabolites.

The investigators found no statistically significant between-group differences on fMRI for the 0- and 1-Back tests. The cannabis group gave fewer correct responses on the 2-Back trial, compared with controls, but had no difference in reaction times.

The researchers found no significant differences in resting state network activation between the two patient groups. During the n-Back test, all patients activated prefrontal, anterior cingulate, and posterior parietal circuits. Several secondary regions activated as well on the 0-Back and 2-Back tests, and the activation pattern was more diffuse in the cannabis group.

Parietal and anterior cingulate activations were only present in the cannabis group for both tasks, according to the investigators. Frontal activation was more prominent in the cannabis group across tasks.

—Erik Greb

Patients with multiple sclerosis (MS) who smoke marijuana regularly have more cognitive deficits than patients with MS who do not smoke marijuana, according to research published May 27 in Neurology. Marijuana use may be associated with impairments in information processing speed, visual memory, and working memory among these individuals.

In a cross-sectional study, cannabis users had more diffuse cerebral activation during a test of working memory, compared with nonusers. The cannabis users also had increased activation in parietal and anterior cingulate brain regions implicated in working memory, relative to nonusers.

But investigators found no differences in brain structure between the study groups, and this finding is consistent with the results of cannabis imaging studies in healthy subjects.

Subjects Underwent Imaging and Neuropsychologic Tests
Bennis Pavisian, research assistant at Sunnybrook Hospital in Toronto, and colleagues recruited 39 patients (ages 18 to 60) with a confirmed diagnosis of MS for their study. They enrolled 20 participants who regularly used cannabis and whose urine tested positive for cannabis metabolites. The investigators asked participants not to use cannabis for 12 hours before the trial. Nineteen patients with MS who had never used cannabis were matched to the other participants using demographic and disease-related variables.

All participants underwent the Brief Repeatable Battery of Neuropsychological Tests in MS, which includes measures of verbal and visual memory, information processing speed, and attention.

The researchers assessed patients’ premorbid IQ with the Wechsler Test of Adult Reading, measured anxiety and depression with the Hospital Anxiety and Depression Scale, and gauged fatigue with the modified Fatigue Impact Scale.

All subjects also underwent the n-Back test of working memory, which had been modified to avoid verbal responses.

The investigators performed fMRI while the participants were taking the n-Back test. They also collected resting-state fMRI and structural MRI data, including lesion and normal-appearing brain tissue volumes and diffusion tensor imaging metrics.

Brain Activation Was More Diffuse Among Marijuana Users
Patients who used cannabis performed worse on the two-second Paced Auditory Serial Addition Test and the 10/36 Spatial Recall Test. Both groups had similar scores on the tests of fatigue, anxiety, and depression. Global cognitive impairment did not correlate with frequency of cannabis use or urine concentration of metabolites.

The investigators found no statistically significant between-group differences on fMRI for the 0- and 1-Back tests. The cannabis group gave fewer correct responses on the 2-Back trial, compared with controls, but had no difference in reaction times.

The researchers found no significant differences in resting state network activation between the two patient groups. During the n-Back test, all patients activated prefrontal, anterior cingulate, and posterior parietal circuits. Several secondary regions activated as well on the 0-Back and 2-Back tests, and the activation pattern was more diffuse in the cannabis group.

Parietal and anterior cingulate activations were only present in the cannabis group for both tasks, according to the investigators. Frontal activation was more prominent in the cannabis group across tasks.

—Erik Greb

The recent upsurge in medical and recreational marijuana laws is creating novel public health concerns for physicians, health advocates, and state regulators alike. Implications of the new laws include packaging risks, accessibility to children, dosage dangers, and the potential for greater drug-related traffic injuries.

Now "is really the time for public health [leaders] to engage on some of these issues" surrounding changes in state laws regarding marijuana use, Colorado Assistant Attorney General Eric Kuhn said during an American Society of Law, Medicine, and Ethics webinar on the expansion of medical marijuana laws. Twenty-one states and the District of Columbia have legalized medical marijuana, and eight other states are considering legislation in 2014. Two states – Colorado and Washington – have legalized recreational use of marijuana. Most recently, Florida legislators overwhelmingly voted in May to legalize a strain of marijuana for limited medicinal use. The bill is now in the hands of Florida Gov. Rick Scott.

Courtesy Wikimedia Commons/Coaster420/Creative Commons License

Health challenges include how best to regulate the drug and to ensure that accessibility does not lead to related harms. Purity and packaging of marijuana are already posing significant worries for states that allow use of the drug, said Mr. Kuhn, who is a National Attorneys General Training and Research Institute/Robert Wood Johnson Foundation public health fellow and the author of a paper about public health issues related to marijuana legalization.

Marijuana samples "have been found to be contaminated with pesticides, herbicides, mold, fungus, bacteria, viruses and other contaminants," he said. Further, "a public health department can’t certify that a product, inherently adulterated with a schedule I substance, is pure."

"The emerging hazards of edibles [are] just beginning to get recognition," Gordon Smith, professor of epidemiology and public health at the University of Maryland, Baltimore, said during the webinar. Of particular concern is the inability to regulate dose. "The standard dose might be an eighth of a brownie. ... Who on earth eats an eighth of a brownie?

Edibles also pose driving risks. "You may start driving and feel fine and then a half an hour later, once the edible starts to get absorbed and have an effect, you start to become very intoxicated," Mr. Smith said. "You really can’t control the dosage."

Some marijuana packages have been labeled to resemble candy and have names similar to those of candy bars. A 2013 analysis of a large Colorado children’s hospital showed that before Sept. 30, 2009, there were zero cases of marijuana ingestion by pediatric patients. After that time, there were 14 cases of marijuana ingestions by children at the hospital, according to a study published in JAMA Pediatrics (2013;167:630-3). The study was conducted before the state’s January recreational marijuana law went into effect but after medical marijuana was decriminalized.

Physicians and health centers are integral to research and safety analyses of medical and recreational marijuana use, health experts said. For instance, more marijuana testing of injured patients by emergency care providers is necessary to determine the role cannabis is playing in traffic crashes, Mr. Smith said.

The recent upsurge in medical and recreational marijuana laws is creating novel public health concerns for physicians, health advocates, and state regulators alike. Implications of the new laws include packaging risks, accessibility to children, dosage dangers, and the potential for greater drug-related traffic injuries.

Now "is really the time for public health [leaders] to engage on some of these issues" surrounding changes in state laws regarding marijuana use, Colorado Assistant Attorney General Eric Kuhn said during an American Society of Law, Medicine, and Ethics webinar on the expansion of medical marijuana laws. Twenty-one states and the District of Columbia have legalized medical marijuana, and eight other states are considering legislation in 2014. Two states – Colorado and Washington – have legalized recreational use of marijuana. Most recently, Florida legislators overwhelmingly voted in May to legalize a strain of marijuana for limited medicinal use. The bill is now in the hands of Florida Gov. Rick Scott.

Courtesy Wikimedia Commons/Coaster420/Creative Commons License

Health challenges include how best to regulate the drug and to ensure that accessibility does not lead to related harms. Purity and packaging of marijuana are already posing significant worries for states that allow use of the drug, said Mr. Kuhn, who is a National Attorneys General Training and Research Institute/Robert Wood Johnson Foundation public health fellow and the author of a paper about public health issues related to marijuana legalization.

Marijuana samples "have been found to be contaminated with pesticides, herbicides, mold, fungus, bacteria, viruses and other contaminants," he said. Further, "a public health department can’t certify that a product, inherently adulterated with a schedule I substance, is pure."

"The emerging hazards of edibles [are] just beginning to get recognition," Gordon Smith, professor of epidemiology and public health at the University of Maryland, Baltimore, said during the webinar. Of particular concern is the inability to regulate dose. "The standard dose might be an eighth of a brownie. ... Who on earth eats an eighth of a brownie?

Edibles also pose driving risks. "You may start driving and feel fine and then a half an hour later, once the edible starts to get absorbed and have an effect, you start to become very intoxicated," Mr. Smith said. "You really can’t control the dosage."

Some marijuana packages have been labeled to resemble candy and have names similar to those of candy bars. A 2013 analysis of a large Colorado children’s hospital showed that before Sept. 30, 2009, there were zero cases of marijuana ingestion by pediatric patients. After that time, there were 14 cases of marijuana ingestions by children at the hospital, according to a study published in JAMA Pediatrics (2013;167:630-3). The study was conducted before the state’s January recreational marijuana law went into effect but after medical marijuana was decriminalized.

Physicians and health centers are integral to research and safety analyses of medical and recreational marijuana use, health experts said. For instance, more marijuana testing of injured patients by emergency care providers is necessary to determine the role cannabis is playing in traffic crashes, Mr. Smith said.

The recent upsurge in medical and recreational marijuana laws is creating novel public health concerns for physicians, health advocates, and state regulators alike. Implications of the new laws include packaging risks, accessibility to children, dosage dangers, and the potential for greater drug-related traffic injuries.

Now "is really the time for public health [leaders] to engage on some of these issues" surrounding changes in state laws regarding marijuana use, Colorado Assistant Attorney General Eric Kuhn said during an American Society of Law, Medicine, and Ethics webinar on the expansion of medical marijuana laws. Twenty-one states and the District of Columbia have legalized medical marijuana, and eight other states are considering legislation in 2014. Two states – Colorado and Washington – have legalized recreational use of marijuana. Most recently, Florida legislators overwhelmingly voted in May to legalize a strain of marijuana for limited medicinal use. The bill is now in the hands of Florida Gov. Rick Scott.

Courtesy Wikimedia Commons/Coaster420/Creative Commons License

Health challenges include how best to regulate the drug and to ensure that accessibility does not lead to related harms. Purity and packaging of marijuana are already posing significant worries for states that allow use of the drug, said Mr. Kuhn, who is a National Attorneys General Training and Research Institute/Robert Wood Johnson Foundation public health fellow and the author of a paper about public health issues related to marijuana legalization.

Marijuana samples "have been found to be contaminated with pesticides, herbicides, mold, fungus, bacteria, viruses and other contaminants," he said. Further, "a public health department can’t certify that a product, inherently adulterated with a schedule I substance, is pure."

"The emerging hazards of edibles [are] just beginning to get recognition," Gordon Smith, professor of epidemiology and public health at the University of Maryland, Baltimore, said during the webinar. Of particular concern is the inability to regulate dose. "The standard dose might be an eighth of a brownie. ... Who on earth eats an eighth of a brownie?

Edibles also pose driving risks. "You may start driving and feel fine and then a half an hour later, once the edible starts to get absorbed and have an effect, you start to become very intoxicated," Mr. Smith said. "You really can’t control the dosage."

Some marijuana packages have been labeled to resemble candy and have names similar to those of candy bars. A 2013 analysis of a large Colorado children’s hospital showed that before Sept. 30, 2009, there were zero cases of marijuana ingestion by pediatric patients. After that time, there were 14 cases of marijuana ingestions by children at the hospital, according to a study published in JAMA Pediatrics (2013;167:630-3). The study was conducted before the state’s January recreational marijuana law went into effect but after medical marijuana was decriminalized.

Physicians and health centers are integral to research and safety analyses of medical and recreational marijuana use, health experts said. For instance, more marijuana testing of injured patients by emergency care providers is necessary to determine the role cannabis is playing in traffic crashes, Mr. Smith said.

DALLAS – Constraint-induced movement therapy – a technique fairly well known for stroke – helps patients with hemiparetic multiple sclerosis, too.

Instead of favoring their good arm, patients are taught to use their affected arm. Once they learn how, the results seem to be self-perpetuating. That might be why Dr. Victor W. Mark and his colleagues at the University of Alabama at Birmingham found that the benefits of even a 10-day course of therapy persist for several years. They also found that constraint-induced movement therapy appears to help restore brain volume lost to MS.

Dr. Mark explained the technique and his findings at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

DALLAS – Constraint-induced movement therapy – a technique fairly well known for stroke – helps patients with hemiparetic multiple sclerosis, too.

Instead of favoring their good arm, patients are taught to use their affected arm. Once they learn how, the results seem to be self-perpetuating. That might be why Dr. Victor W. Mark and his colleagues at the University of Alabama at Birmingham found that the benefits of even a 10-day course of therapy persist for several years. They also found that constraint-induced movement therapy appears to help restore brain volume lost to MS.

Dr. Mark explained the technique and his findings at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.

DALLAS – Constraint-induced movement therapy – a technique fairly well known for stroke – helps patients with hemiparetic multiple sclerosis, too.

Instead of favoring their good arm, patients are taught to use their affected arm. Once they learn how, the results seem to be self-perpetuating. That might be why Dr. Victor W. Mark and his colleagues at the University of Alabama at Birmingham found that the benefits of even a 10-day course of therapy persist for several years. They also found that constraint-induced movement therapy appears to help restore brain volume lost to MS.

Dr. Mark explained the technique and his findings at a meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.