Multiple Sclerosis

COPENHAGEN—Terifluno­mide (14 mg and 7 mg) is safe and effective in the treatment of patients with clinically isolated syndrome, according to TOPIC trial data presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

“These findings highlight the ability of early intervention with teriflunomide to delay onset of MS symptoms,” said Aaron E. Miller, MD, Professor of Neurology at the Icahn School of Medicine at Mount Sinai, New York, and his study collaborators. “To date, all teriflunomide phase III studies have shown consistent safety and efficacy, and greater efficacy for a 14-mg dose.”

Teriflunomide is a novel, once-daily, oral immunomodulator approved in the United States, Argentina, and Australia for the treatment of relapsing-remitting MS. Prior clinical studies of teriflunomide in patients with relapsing-remitting MS (TEMSO and TOWER) showed consistent efficacy across key clinical measures and a well-characterized safety profile. TOPIC was a phase III clinical trial conducted to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of MS (clinically isolated syndrome).

In TOPIC, a double-blind, placebo-controlled, parallel-group study, 618 patients with clinically isolated syndrome were enrolled from February 2008 to September 2012 (projected end date, December 2012) and randomized to placebo, teriflunomide 7 mg, or teriflunomide 14 mg. TOPIC ended three months early as revised diagnostic criteria enabled earlier diagnosis of MS. The primary and key secondary end points were conversion to clinically definite MS and occurrence of a new clinical relapse or MRI lesion. Other efficacy end points and safety and tolerability were also assessed.

Baseline characteristics were generally well balanced among the treatment groups. Of the randomized population (n = 618), 59.1% had monofocal and 40.9% had multifocal lesion presentation, and 31.4% had one or more gadolinium-enhancing lesions. Median time since first neurologic event was two months.

Compared with placebo, teriflunomide 14 mg reduced the risk of conversion to clinically definite MS by 42.6%, with a probability of conversion to clinically definite MS at 108 weeks of 24.0% (probability for placebo group, 35.9%). Teriflunomide 14 mg also reduced the risk of occurrence of new relapse or new MRI lesion by 34.9%. As measured by MRI over the two-year study period, patients treated with teriflunomide 14 mg had a 5% increase in total lesion volume, compared with a 28% increase among patients treated with placebo. In addition, patients treated with teriflunomide 14 mg had a 59% reduction in gadolinium-enhancing T1 lesions, compared with patients receiving placebo.

Teriflunomide 7 mg reduced the risk of conversion to clinically definite MS by 37.2% (108-week probability, 27.6%) and the risk of occurrence of new relapse or new MRI lesion by 31.4%. The occurrence of adverse events was similar across treatment groups. The most common adverse events reported more frequently in the teriflunomide arms included alanine aminotransferase elevation, headache, hair thinning (14 mg only), diarrhea, and paresthesia.

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Terifluno­mide (14 mg and 7 mg) is safe and effective in the treatment of patients with clinically isolated syndrome, according to TOPIC trial data presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

“These findings highlight the ability of early intervention with teriflunomide to delay onset of MS symptoms,” said Aaron E. Miller, MD, Professor of Neurology at the Icahn School of Medicine at Mount Sinai, New York, and his study collaborators. “To date, all teriflunomide phase III studies have shown consistent safety and efficacy, and greater efficacy for a 14-mg dose.”

Teriflunomide is a novel, once-daily, oral immunomodulator approved in the United States, Argentina, and Australia for the treatment of relapsing-remitting MS. Prior clinical studies of teriflunomide in patients with relapsing-remitting MS (TEMSO and TOWER) showed consistent efficacy across key clinical measures and a well-characterized safety profile. TOPIC was a phase III clinical trial conducted to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of MS (clinically isolated syndrome).

In TOPIC, a double-blind, placebo-controlled, parallel-group study, 618 patients with clinically isolated syndrome were enrolled from February 2008 to September 2012 (projected end date, December 2012) and randomized to placebo, teriflunomide 7 mg, or teriflunomide 14 mg. TOPIC ended three months early as revised diagnostic criteria enabled earlier diagnosis of MS. The primary and key secondary end points were conversion to clinically definite MS and occurrence of a new clinical relapse or MRI lesion. Other efficacy end points and safety and tolerability were also assessed.

Baseline characteristics were generally well balanced among the treatment groups. Of the randomized population (n = 618), 59.1% had monofocal and 40.9% had multifocal lesion presentation, and 31.4% had one or more gadolinium-enhancing lesions. Median time since first neurologic event was two months.

Compared with placebo, teriflunomide 14 mg reduced the risk of conversion to clinically definite MS by 42.6%, with a probability of conversion to clinically definite MS at 108 weeks of 24.0% (probability for placebo group, 35.9%). Teriflunomide 14 mg also reduced the risk of occurrence of new relapse or new MRI lesion by 34.9%. As measured by MRI over the two-year study period, patients treated with teriflunomide 14 mg had a 5% increase in total lesion volume, compared with a 28% increase among patients treated with placebo. In addition, patients treated with teriflunomide 14 mg had a 59% reduction in gadolinium-enhancing T1 lesions, compared with patients receiving placebo.

Teriflunomide 7 mg reduced the risk of conversion to clinically definite MS by 37.2% (108-week probability, 27.6%) and the risk of occurrence of new relapse or new MRI lesion by 31.4%. The occurrence of adverse events was similar across treatment groups. The most common adverse events reported more frequently in the teriflunomide arms included alanine aminotransferase elevation, headache, hair thinning (14 mg only), diarrhea, and paresthesia.

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—Terifluno­mide (14 mg and 7 mg) is safe and effective in the treatment of patients with clinically isolated syndrome, according to TOPIC trial data presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

“These findings highlight the ability of early intervention with teriflunomide to delay onset of MS symptoms,” said Aaron E. Miller, MD, Professor of Neurology at the Icahn School of Medicine at Mount Sinai, New York, and his study collaborators. “To date, all teriflunomide phase III studies have shown consistent safety and efficacy, and greater efficacy for a 14-mg dose.”

Teriflunomide is a novel, once-daily, oral immunomodulator approved in the United States, Argentina, and Australia for the treatment of relapsing-remitting MS. Prior clinical studies of teriflunomide in patients with relapsing-remitting MS (TEMSO and TOWER) showed consistent efficacy across key clinical measures and a well-characterized safety profile. TOPIC was a phase III clinical trial conducted to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of MS (clinically isolated syndrome).

In TOPIC, a double-blind, placebo-controlled, parallel-group study, 618 patients with clinically isolated syndrome were enrolled from February 2008 to September 2012 (projected end date, December 2012) and randomized to placebo, teriflunomide 7 mg, or teriflunomide 14 mg. TOPIC ended three months early as revised diagnostic criteria enabled earlier diagnosis of MS. The primary and key secondary end points were conversion to clinically definite MS and occurrence of a new clinical relapse or MRI lesion. Other efficacy end points and safety and tolerability were also assessed.

Baseline characteristics were generally well balanced among the treatment groups. Of the randomized population (n = 618), 59.1% had monofocal and 40.9% had multifocal lesion presentation, and 31.4% had one or more gadolinium-enhancing lesions. Median time since first neurologic event was two months.

Compared with placebo, teriflunomide 14 mg reduced the risk of conversion to clinically definite MS by 42.6%, with a probability of conversion to clinically definite MS at 108 weeks of 24.0% (probability for placebo group, 35.9%). Teriflunomide 14 mg also reduced the risk of occurrence of new relapse or new MRI lesion by 34.9%. As measured by MRI over the two-year study period, patients treated with teriflunomide 14 mg had a 5% increase in total lesion volume, compared with a 28% increase among patients treated with placebo. In addition, patients treated with teriflunomide 14 mg had a 59% reduction in gadolinium-enhancing T1 lesions, compared with patients receiving placebo.

Teriflunomide 7 mg reduced the risk of conversion to clinically definite MS by 37.2% (108-week probability, 27.6%) and the risk of occurrence of new relapse or new MRI lesion by 31.4%. The occurrence of adverse events was similar across treatment groups. The most common adverse events reported more frequently in the teriflunomide arms included alanine aminotransferase elevation, headache, hair thinning (14 mg only), diarrhea, and paresthesia.

—Glenn S. Williams
Vice President/Group Editor

COPENHAGEN—The many drugs in development for multiple sclerosis (MS) have various modes of action and could increase patients’ treatment options, according to an overview presented at the 29th Congress of the European Committee for Treatment and Research in MS. If these drugs reach the market, they may make it difficult for neurologists to stratify patients to various treatment regimens, but they will open new possibilities such as combination therapies, said Tobias Derfuss, MD.

Laquinimod Reduced Disability Progression
Two recently completed phase III trials found that laquinimod, a drug that appeared to promote remyelination in animal models, reduced patients’ annualized relapse rate by 20%. The drug also was associated with a “surprising” 46% reduction in disability progression, said Dr. Derfuss, Cohead of the Outpatient Care Unit and the Neuroimmunological Research Group at the University Hospital Basel. “You expect this effect on disability progression only if you also have a strong effect on the inflammatory components or [if] the drug has an impact on neuroprotection,” he said.

In addition, laquinimod reduced patients’ rate of brain atrophy by 30% during a 24-month period, which indicated that the drug might have a neuroprotective effect. New trials are required to identify the optimal dose and determine whether the drug could be part of a combination therapy.

Siponimod Decreased the Number of Unique Active Lesions
Siponimod is an oral compound in development that acts on the sphingosine-1-phosphate receptor. A phase II trial that compared siponimod to placebo in patients with relapsing-remitting MS suggested that 2 mg was the most effective dose of the drug. Compared with placebo, siponimod reduced unique active lesions at three months.

Investigators are recruiting participants for a phase III trial of siponimod in patients with secondary progressive MS. The trial will continue until a certain number of patients have three-month confirmed disability progression, which is the primary end point. When patients have six-month confirmed disability progression, they will be given the option of switching to open-label treatment. “This trial is a very good option for patients with secondary progressive MS,” said Dr. Derfuss.

Simvastatin May Reduce Brain Atrophy
Researchers have investigated the efficacy of statins in treating relapsing-remitting MS, and a double blind placebo-controlled trial in 2012 evaluated the efficacy of 80 mg/day of simvastatin in patients with secondary progressive MS. The drug was associated with significant reduction in brain atrophy, as well as with reductions in Expanded Disability Status Scale score and the MS Impact Scale, a patient-related outcome.

The results are surprising, in light of the trial’s small patient population, said Dr. Derfuss. In all, 140 patients participated in the trial, which lasted for two years. “We know from other trials in secondary progressive MS [that] it might take longer to see the effect,” said Dr. Derfuss. But because simvastatin no longer has patent protection, he added, pharmaceutical companies may be unwilling to conduct larger phase III trials, which means that MS societies and independent research organizations may have to provide the necessary funding.

Monoclonal Antibodies May Improve Patients’ Outcomes
Several monoclonal anti­bodies in development also show promise for the treatment of MS. Investigators recently completed a phase II trial that tested two doses of daclizumab, an IL-2 receptor antagonist, for one year. Compared with placebo, daclizumab reduced patients’ annualized relapse rate by more than 50%. An extension study and another phase IIb trial have supported the treatment’s efficacy. Daclizumab is a “promising drug” that has an “impressive effect on disability progression” within a short time, said Dr. Derfuss.

Secukinumab is a fully humanized antibody against the IL-17A cytokine. Patients in a small trial received 10 mg/kg/day of secukinumab. Despite the trial’s brief duration, researchers observed a significant reduction in new gadolinium-enhancing lesions among patients receiving secukinumab. Patients in the treatment arm also had a reduction in relapse rates, but it was not statistically significant. Investigators are recruiting patients for a second, larger phase II trial.

Ocrelizumab, a third antibody, depletes the body’s B-cells. A recent phase II trial compared ocrelizumab with interferon beta-1a and placebo. After eight weeks, patients who received ocrelizumab had a significant reduction in gadolinium-enhancing lesions, compared with patients receiving placebo and those receiving interferon. Ocrelizumab also reduced relapse rates. Two phase III trials are studying ocrelizumab for primary progressive MS, and one trial is evaluating ocrelizumab as a treatment for relapsing-remitting MS.

—Erik Greb
Senior Associate Editor

COPENHAGEN—The many drugs in development for multiple sclerosis (MS) have various modes of action and could increase patients’ treatment options, according to an overview presented at the 29th Congress of the European Committee for Treatment and Research in MS. If these drugs reach the market, they may make it difficult for neurologists to stratify patients to various treatment regimens, but they will open new possibilities such as combination therapies, said Tobias Derfuss, MD.

Laquinimod Reduced Disability Progression
Two recently completed phase III trials found that laquinimod, a drug that appeared to promote remyelination in animal models, reduced patients’ annualized relapse rate by 20%. The drug also was associated with a “surprising” 46% reduction in disability progression, said Dr. Derfuss, Cohead of the Outpatient Care Unit and the Neuroimmunological Research Group at the University Hospital Basel. “You expect this effect on disability progression only if you also have a strong effect on the inflammatory components or [if] the drug has an impact on neuroprotection,” he said.

In addition, laquinimod reduced patients’ rate of brain atrophy by 30% during a 24-month period, which indicated that the drug might have a neuroprotective effect. New trials are required to identify the optimal dose and determine whether the drug could be part of a combination therapy.

Siponimod Decreased the Number of Unique Active Lesions
Siponimod is an oral compound in development that acts on the sphingosine-1-phosphate receptor. A phase II trial that compared siponimod to placebo in patients with relapsing-remitting MS suggested that 2 mg was the most effective dose of the drug. Compared with placebo, siponimod reduced unique active lesions at three months.

Investigators are recruiting participants for a phase III trial of siponimod in patients with secondary progressive MS. The trial will continue until a certain number of patients have three-month confirmed disability progression, which is the primary end point. When patients have six-month confirmed disability progression, they will be given the option of switching to open-label treatment. “This trial is a very good option for patients with secondary progressive MS,” said Dr. Derfuss.

Simvastatin May Reduce Brain Atrophy
Researchers have investigated the efficacy of statins in treating relapsing-remitting MS, and a double blind placebo-controlled trial in 2012 evaluated the efficacy of 80 mg/day of simvastatin in patients with secondary progressive MS. The drug was associated with significant reduction in brain atrophy, as well as with reductions in Expanded Disability Status Scale score and the MS Impact Scale, a patient-related outcome.

The results are surprising, in light of the trial’s small patient population, said Dr. Derfuss. In all, 140 patients participated in the trial, which lasted for two years. “We know from other trials in secondary progressive MS [that] it might take longer to see the effect,” said Dr. Derfuss. But because simvastatin no longer has patent protection, he added, pharmaceutical companies may be unwilling to conduct larger phase III trials, which means that MS societies and independent research organizations may have to provide the necessary funding.

Monoclonal Antibodies May Improve Patients’ Outcomes
Several monoclonal anti­bodies in development also show promise for the treatment of MS. Investigators recently completed a phase II trial that tested two doses of daclizumab, an IL-2 receptor antagonist, for one year. Compared with placebo, daclizumab reduced patients’ annualized relapse rate by more than 50%. An extension study and another phase IIb trial have supported the treatment’s efficacy. Daclizumab is a “promising drug” that has an “impressive effect on disability progression” within a short time, said Dr. Derfuss.

Secukinumab is a fully humanized antibody against the IL-17A cytokine. Patients in a small trial received 10 mg/kg/day of secukinumab. Despite the trial’s brief duration, researchers observed a significant reduction in new gadolinium-enhancing lesions among patients receiving secukinumab. Patients in the treatment arm also had a reduction in relapse rates, but it was not statistically significant. Investigators are recruiting patients for a second, larger phase II trial.

Ocrelizumab, a third antibody, depletes the body’s B-cells. A recent phase II trial compared ocrelizumab with interferon beta-1a and placebo. After eight weeks, patients who received ocrelizumab had a significant reduction in gadolinium-enhancing lesions, compared with patients receiving placebo and those receiving interferon. Ocrelizumab also reduced relapse rates. Two phase III trials are studying ocrelizumab for primary progressive MS, and one trial is evaluating ocrelizumab as a treatment for relapsing-remitting MS.

—Erik Greb
Senior Associate Editor

COPENHAGEN—The many drugs in development for multiple sclerosis (MS) have various modes of action and could increase patients’ treatment options, according to an overview presented at the 29th Congress of the European Committee for Treatment and Research in MS. If these drugs reach the market, they may make it difficult for neurologists to stratify patients to various treatment regimens, but they will open new possibilities such as combination therapies, said Tobias Derfuss, MD.

Laquinimod Reduced Disability Progression
Two recently completed phase III trials found that laquinimod, a drug that appeared to promote remyelination in animal models, reduced patients’ annualized relapse rate by 20%. The drug also was associated with a “surprising” 46% reduction in disability progression, said Dr. Derfuss, Cohead of the Outpatient Care Unit and the Neuroimmunological Research Group at the University Hospital Basel. “You expect this effect on disability progression only if you also have a strong effect on the inflammatory components or [if] the drug has an impact on neuroprotection,” he said.

In addition, laquinimod reduced patients’ rate of brain atrophy by 30% during a 24-month period, which indicated that the drug might have a neuroprotective effect. New trials are required to identify the optimal dose and determine whether the drug could be part of a combination therapy.

Siponimod Decreased the Number of Unique Active Lesions
Siponimod is an oral compound in development that acts on the sphingosine-1-phosphate receptor. A phase II trial that compared siponimod to placebo in patients with relapsing-remitting MS suggested that 2 mg was the most effective dose of the drug. Compared with placebo, siponimod reduced unique active lesions at three months.

Investigators are recruiting participants for a phase III trial of siponimod in patients with secondary progressive MS. The trial will continue until a certain number of patients have three-month confirmed disability progression, which is the primary end point. When patients have six-month confirmed disability progression, they will be given the option of switching to open-label treatment. “This trial is a very good option for patients with secondary progressive MS,” said Dr. Derfuss.

Simvastatin May Reduce Brain Atrophy
Researchers have investigated the efficacy of statins in treating relapsing-remitting MS, and a double blind placebo-controlled trial in 2012 evaluated the efficacy of 80 mg/day of simvastatin in patients with secondary progressive MS. The drug was associated with significant reduction in brain atrophy, as well as with reductions in Expanded Disability Status Scale score and the MS Impact Scale, a patient-related outcome.

The results are surprising, in light of the trial’s small patient population, said Dr. Derfuss. In all, 140 patients participated in the trial, which lasted for two years. “We know from other trials in secondary progressive MS [that] it might take longer to see the effect,” said Dr. Derfuss. But because simvastatin no longer has patent protection, he added, pharmaceutical companies may be unwilling to conduct larger phase III trials, which means that MS societies and independent research organizations may have to provide the necessary funding.

Monoclonal Antibodies May Improve Patients’ Outcomes
Several monoclonal anti­bodies in development also show promise for the treatment of MS. Investigators recently completed a phase II trial that tested two doses of daclizumab, an IL-2 receptor antagonist, for one year. Compared with placebo, daclizumab reduced patients’ annualized relapse rate by more than 50%. An extension study and another phase IIb trial have supported the treatment’s efficacy. Daclizumab is a “promising drug” that has an “impressive effect on disability progression” within a short time, said Dr. Derfuss.

Secukinumab is a fully humanized antibody against the IL-17A cytokine. Patients in a small trial received 10 mg/kg/day of secukinumab. Despite the trial’s brief duration, researchers observed a significant reduction in new gadolinium-enhancing lesions among patients receiving secukinumab. Patients in the treatment arm also had a reduction in relapse rates, but it was not statistically significant. Investigators are recruiting patients for a second, larger phase II trial.

Ocrelizumab, a third antibody, depletes the body’s B-cells. A recent phase II trial compared ocrelizumab with interferon beta-1a and placebo. After eight weeks, patients who received ocrelizumab had a significant reduction in gadolinium-enhancing lesions, compared with patients receiving placebo and those receiving interferon. Ocrelizumab also reduced relapse rates. Two phase III trials are studying ocrelizumab for primary progressive MS, and one trial is evaluating ocrelizumab as a treatment for relapsing-remitting MS.

—Erik Greb
Senior Associate Editor

AUSTIN—Adjusting the ketogenic diet is helpful in one of five children with epilepsy, researchers reported at the 2013 Annual Meeting of the Child Neurology Society.

“Medication adjustment and dietary modification lead to similar outcomes,” stated Eric Kossoff, MD, Assistant Professor of Neurology and Pediatrics at Johns Hopkins Children’s Center in Baltimore, and colleagues. “Therefore, both [tactics] can be tried if the ketogenic diet is not meeting seizure-control expectations.”

The findings are based on a retrospective review of 200 children with epilepsy who had begun the ketogenic diet at the Johns Hopkins Hospital between October 2007 and June 2013. Dr. Kossoff’s group identified 10 commonly implemented dietary and supplement changes among the children. The investigators also reviewed medication adjustments in the children, as well as patient records during the course of adherence to the ketogenic diet for as many as four interventions per child. Greater than 50% seizure reduction after a change was defined as success, according to the study authors.

A total of 156 children (78%) had at least one intervention, and 391 distinct and occasionally concurrent interventions were recorded, of which 265 were made specifically for seizure control, noted Dr. Kossoff.

“Overall, there was an 18% chance that any intervention would be successful, but only a 3% chance of resultant seizure freedom,” reported the researchers. “The likelihood of success did not decrease with each subsequent intervention. There was a trend toward medication adjustments being more successful than dietary modifications (24% vs 15%, respectively).”

Analgesic Overuse May Worsen Chronic Post-Traumatic Headaches in Adolescents With Concussion
Excessive use of analgesics may exacerbate post-traumatic headaches among adolescents who have had a concussion, investigators reported.

“Analgesics should be minimized or discontinued when headaches continue several weeks following concussion,” recommended Geoffrey L. Heyer, MD, of the Division of Pediatric Neurology, Nationwide Children’s Hospital in Columbus, Ohio, and colleagues.

The researchers conducted a retrospective review of 104 adolescents with concussion who had been referred to a pediatric headache clinic for chronic post-traumatic headaches of three to 12 months in duration. The study authors compared concussion symptoms, headache symptoms before and after concussion, demographic data, and headache outcomes between patients who had probable medication-overuse headache and those who did not have probable medication-overuse headache.

A total of 77 patients had chronic post-traumatic headache between three and 12 months, and 54 patients (70%) met the criteria for probable medication-overuse headache. The investigators found that patients with medication overuse were more likely to have had daily headaches, to be female, to have had nausea or throbbing associated with their headaches, to have had increased irritability following concussion, and to have had a longer interval between injury and neurologic evaluation.

“Of the patients with medication overuse, 37 (68.5%) had resolution of headaches or improvements to preconcussion headache patterns after discontinuing analgesics, seven (13%) had no change in headaches or worsening of headaches after discontinuing analgesics, and 10 (18.5%) did not discontinue analgesics or were lost to follow-up,” stated Dr. Heyer.

2010 McDonald Criteria Are Effective for Early Diagnosis of Pediatric MS
The 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis (MS) may have a higher sensitivity for diagnosing pediatric MS, compared with the 2005 criteria. The revised criteria thus could allow for earlier initiation of disease-modifying therapy, researchers reported.

Mitchel T. Williams, MD, Pediatric Neurologist at the Children’s Hospital of Michigan in Detroit, and colleagues conducted a retrospective study of 25 children who had been diagnosed with MS at the Children’s Hospital of Michigan from 2005 through early 2013.

The researchers applied the 2005 and 2010 McDonald criteria based on neuroimaging findings as well as initial clinical presentation. The investigators also analyzed demographic data and compared those data with those of previous pediatric MS cohorts.

The median age at presentation, sex ratio, clinical symptoms, and relapse rate among the participants were comparable to those in previously published data, except for a high rate of African Americans (64%) among the 25 children.

The researchers found that the initial MS diagnosis rate based on the 2005 McDonald criteria was 32%, compared with a rate of 92% using the 2010 McDonald criteria. The mean time after initial symptom presentation until the 2005 criteria for MS were met was 5.0 months, compared with 0.7 months for the 2010 McDonald criteria.

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

—Colby Stong
Editor

AUSTIN—Adjusting the ketogenic diet is helpful in one of five children with epilepsy, researchers reported at the 2013 Annual Meeting of the Child Neurology Society.

“Medication adjustment and dietary modification lead to similar outcomes,” stated Eric Kossoff, MD, Assistant Professor of Neurology and Pediatrics at Johns Hopkins Children’s Center in Baltimore, and colleagues. “Therefore, both [tactics] can be tried if the ketogenic diet is not meeting seizure-control expectations.”

The findings are based on a retrospective review of 200 children with epilepsy who had begun the ketogenic diet at the Johns Hopkins Hospital between October 2007 and June 2013. Dr. Kossoff’s group identified 10 commonly implemented dietary and supplement changes among the children. The investigators also reviewed medication adjustments in the children, as well as patient records during the course of adherence to the ketogenic diet for as many as four interventions per child. Greater than 50% seizure reduction after a change was defined as success, according to the study authors.

A total of 156 children (78%) had at least one intervention, and 391 distinct and occasionally concurrent interventions were recorded, of which 265 were made specifically for seizure control, noted Dr. Kossoff.

“Overall, there was an 18% chance that any intervention would be successful, but only a 3% chance of resultant seizure freedom,” reported the researchers. “The likelihood of success did not decrease with each subsequent intervention. There was a trend toward medication adjustments being more successful than dietary modifications (24% vs 15%, respectively).”

Analgesic Overuse May Worsen Chronic Post-Traumatic Headaches in Adolescents With Concussion
Excessive use of analgesics may exacerbate post-traumatic headaches among adolescents who have had a concussion, investigators reported.

“Analgesics should be minimized or discontinued when headaches continue several weeks following concussion,” recommended Geoffrey L. Heyer, MD, of the Division of Pediatric Neurology, Nationwide Children’s Hospital in Columbus, Ohio, and colleagues.

The researchers conducted a retrospective review of 104 adolescents with concussion who had been referred to a pediatric headache clinic for chronic post-traumatic headaches of three to 12 months in duration. The study authors compared concussion symptoms, headache symptoms before and after concussion, demographic data, and headache outcomes between patients who had probable medication-overuse headache and those who did not have probable medication-overuse headache.

A total of 77 patients had chronic post-traumatic headache between three and 12 months, and 54 patients (70%) met the criteria for probable medication-overuse headache. The investigators found that patients with medication overuse were more likely to have had daily headaches, to be female, to have had nausea or throbbing associated with their headaches, to have had increased irritability following concussion, and to have had a longer interval between injury and neurologic evaluation.

“Of the patients with medication overuse, 37 (68.5%) had resolution of headaches or improvements to preconcussion headache patterns after discontinuing analgesics, seven (13%) had no change in headaches or worsening of headaches after discontinuing analgesics, and 10 (18.5%) did not discontinue analgesics or were lost to follow-up,” stated Dr. Heyer.

2010 McDonald Criteria Are Effective for Early Diagnosis of Pediatric MS
The 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis (MS) may have a higher sensitivity for diagnosing pediatric MS, compared with the 2005 criteria. The revised criteria thus could allow for earlier initiation of disease-modifying therapy, researchers reported.

Mitchel T. Williams, MD, Pediatric Neurologist at the Children’s Hospital of Michigan in Detroit, and colleagues conducted a retrospective study of 25 children who had been diagnosed with MS at the Children’s Hospital of Michigan from 2005 through early 2013.

The researchers applied the 2005 and 2010 McDonald criteria based on neuroimaging findings as well as initial clinical presentation. The investigators also analyzed demographic data and compared those data with those of previous pediatric MS cohorts.

The median age at presentation, sex ratio, clinical symptoms, and relapse rate among the participants were comparable to those in previously published data, except for a high rate of African Americans (64%) among the 25 children.

The researchers found that the initial MS diagnosis rate based on the 2005 McDonald criteria was 32%, compared with a rate of 92% using the 2010 McDonald criteria. The mean time after initial symptom presentation until the 2005 criteria for MS were met was 5.0 months, compared with 0.7 months for the 2010 McDonald criteria.

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

—Colby Stong
Editor

AUSTIN—Adjusting the ketogenic diet is helpful in one of five children with epilepsy, researchers reported at the 2013 Annual Meeting of the Child Neurology Society.

“Medication adjustment and dietary modification lead to similar outcomes,” stated Eric Kossoff, MD, Assistant Professor of Neurology and Pediatrics at Johns Hopkins Children’s Center in Baltimore, and colleagues. “Therefore, both [tactics] can be tried if the ketogenic diet is not meeting seizure-control expectations.”

The findings are based on a retrospective review of 200 children with epilepsy who had begun the ketogenic diet at the Johns Hopkins Hospital between October 2007 and June 2013. Dr. Kossoff’s group identified 10 commonly implemented dietary and supplement changes among the children. The investigators also reviewed medication adjustments in the children, as well as patient records during the course of adherence to the ketogenic diet for as many as four interventions per child. Greater than 50% seizure reduction after a change was defined as success, according to the study authors.

A total of 156 children (78%) had at least one intervention, and 391 distinct and occasionally concurrent interventions were recorded, of which 265 were made specifically for seizure control, noted Dr. Kossoff.

“Overall, there was an 18% chance that any intervention would be successful, but only a 3% chance of resultant seizure freedom,” reported the researchers. “The likelihood of success did not decrease with each subsequent intervention. There was a trend toward medication adjustments being more successful than dietary modifications (24% vs 15%, respectively).”

Analgesic Overuse May Worsen Chronic Post-Traumatic Headaches in Adolescents With Concussion
Excessive use of analgesics may exacerbate post-traumatic headaches among adolescents who have had a concussion, investigators reported.

“Analgesics should be minimized or discontinued when headaches continue several weeks following concussion,” recommended Geoffrey L. Heyer, MD, of the Division of Pediatric Neurology, Nationwide Children’s Hospital in Columbus, Ohio, and colleagues.

The researchers conducted a retrospective review of 104 adolescents with concussion who had been referred to a pediatric headache clinic for chronic post-traumatic headaches of three to 12 months in duration. The study authors compared concussion symptoms, headache symptoms before and after concussion, demographic data, and headache outcomes between patients who had probable medication-overuse headache and those who did not have probable medication-overuse headache.

A total of 77 patients had chronic post-traumatic headache between three and 12 months, and 54 patients (70%) met the criteria for probable medication-overuse headache. The investigators found that patients with medication overuse were more likely to have had daily headaches, to be female, to have had nausea or throbbing associated with their headaches, to have had increased irritability following concussion, and to have had a longer interval between injury and neurologic evaluation.

“Of the patients with medication overuse, 37 (68.5%) had resolution of headaches or improvements to preconcussion headache patterns after discontinuing analgesics, seven (13%) had no change in headaches or worsening of headaches after discontinuing analgesics, and 10 (18.5%) did not discontinue analgesics or were lost to follow-up,” stated Dr. Heyer.

2010 McDonald Criteria Are Effective for Early Diagnosis of Pediatric MS
The 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis (MS) may have a higher sensitivity for diagnosing pediatric MS, compared with the 2005 criteria. The revised criteria thus could allow for earlier initiation of disease-modifying therapy, researchers reported.

Mitchel T. Williams, MD, Pediatric Neurologist at the Children’s Hospital of Michigan in Detroit, and colleagues conducted a retrospective study of 25 children who had been diagnosed with MS at the Children’s Hospital of Michigan from 2005 through early 2013.

The researchers applied the 2005 and 2010 McDonald criteria based on neuroimaging findings as well as initial clinical presentation. The investigators also analyzed demographic data and compared those data with those of previous pediatric MS cohorts.

The median age at presentation, sex ratio, clinical symptoms, and relapse rate among the participants were comparable to those in previously published data, except for a high rate of African Americans (64%) among the 25 children.

The researchers found that the initial MS diagnosis rate based on the 2005 McDonald criteria was 32%, compared with a rate of 92% using the 2010 McDonald criteria. The mean time after initial symptom presentation until the 2005 criteria for MS were met was 5.0 months, compared with 0.7 months for the 2010 McDonald criteria.

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

—Colby Stong
Editor

Dot Test May Gauge the Progression of Dopamine Loss in Parkinson’s Disease
A simple dot test could help gauge the extent of dopamine loss in individuals with Parkinson’s disease, according to a pilot study by a multidisciplinary team of investigators. “It is difficult now to assess the extent of dopamine loss—a hallmark of Parkinson’s disease—in people with the disease,” said Katherine R. Gamble, a doctoral student in psychology at Georgetown University in Washington, DC. “This test, called the Triplets Learning Task (TLT), may provide some help for physicians who treat people with Parkinson’s disease, but we still have much work to do to better understand its utility,” she added.

The TLT tests implicit learning, which occurs without awareness or intent and relies on the caudate nucleus, an area of the brain affected by loss of dopamine. The test is a sequential learning task that does not require complex motor skills. In the TLT, participants see four open circles, and then two red dots appear. Patients are asked to respond when they see a green dot appear. Unknown to them, the location of the first red dot predicts the location of the green dot. Participants learn implicitly where the green dot will appear, and their responses become faster and more accurate.

Previous studies have shown that the caudate region in the brain underlies implicit learning. In the study, participants with Parkinson’s disease implicitly learned the dot pattern with training, but a loss of dopamine appears to negatively affect that learning. “Their performance began to decline toward the end of training, suggesting that people with Parkinson’s disease lack the neural resources in the caudate, such as dopamine, to complete the learning task,” said Ms. Gamble. The current study included 27 patients with Parkinson’s disease. The research team is now testing how implicit learning may differ by different stages of Parkinson’s disease and drug doses.

The Eyes May Help Diagnose Alzheimer’s Disease
The loss of a particular layer of retinal cells may reveal the presence of Alzheimer’s disease and provide a new way to track disease progression, according to an international team of researchers. The investigators examined retinas from the eyes of mice genetically engineered to develop Alzheimer’s disease.

“The retina is an extension of the brain, so it makes sense to see if the same pathologic processes found in an Alzheimer’s brain are also found in the eye,” said R. Scott Turner, MD, PhD, Director of the Memory Disorders Program at Georgetown University Medical Center in Washington, DC. “We know there’s an association between glaucoma and Alzheimer’s disease, in that both are characterized by loss of neurons, but the mechanisms are not clear.” Many researchers increasingly view glaucoma as a neurodegenerative disorder similar to Alzheimer’s disease, he added.

Most of the research to date examining the relationship between glaucoma and Alzheimer’s disease focused on the retinal ganglion cell layer, which transmits visual information via the optic nerve into the brain. Before that transmission happens, though, the retinal ganglion cells receive information from another layer in the retina—the inner nuclear layer.

The researchers examined the thickness of the retina, including the inner nuclear layer (which had not been studied previously in this setting) and the retinal ganglion cell layer. They found a significant loss of thickness in both layers. The inner nuclear layer had a 37% loss of neurons, and the retinal ganglion cell layer had a 49% loss of neurons, compared with healthy, age-matched control mice.

In humans, the structure and thickness of the retina can be readily measured using optical coherence tomography. This new tool is finding an increasing number of applications in research and clinical care, said Dr. Turner.

“This study suggests another path forward in understanding the disease process and could lead to new ways to diagnose or predict Alzheimer’s that could be as simple as looking into the eyes,” said Dr. Turner. “Parallel disease mechanisms suggest that new treatments developed for Alzheimer’s disease may also be useful for glaucoma.”

Research Suggests Warning Signs and Potential Treatments for MS
Recent research is increasing clinicians’ understanding of multiple sclerosis (MS) and may lead to new treatments and management strategies, said investigators. One study has shed light on the way in which antibodies in the bloodstream break through the blood–brain barrier to attack the optic nerves, spinal cord, and brain, causing the symptoms of neuromyelitis optica. Understanding how the antibodies bypass the blood–brain barrier could provide new approaches to treating the disease.

A protein involved in blood clotting might serve as an early biomarker for MS before symptoms occur, said Katerina Akassoglou, PhD, Professor in Residence of Neurology at the University of California, San Francisco School of Medicine. Early detection of the disease could lead to more effective early treatments.

In another study, low levels of a cholesterol protein correlated with the severity of MS. The finding suggests that the protein, which protects against inflammation, may protect against developing MS and may help regenerate damaged neurons, said Lidia Gardner, PhD, Assistant Professor of Neurology at the University of Tennessee in Memphis. Cholesterol drugs thus may be potential treatments for MS.

Researchers found that a type of immune system cell directly targets and damages nerve cell axons, just as MS does. This cell may be a target for new disease-modifying therapies. In addition, researchers have found that when exosomes—tiny, naturally occurring nanovesicles—are produced by dendritic cells and applied to the brain, they can deliver a mixture of proteins and RNAs that promote the regeneration of protective myelin sheaths and guard against MS symptoms.

Dot Test May Gauge the Progression of Dopamine Loss in Parkinson’s Disease
A simple dot test could help gauge the extent of dopamine loss in individuals with Parkinson’s disease, according to a pilot study by a multidisciplinary team of investigators. “It is difficult now to assess the extent of dopamine loss—a hallmark of Parkinson’s disease—in people with the disease,” said Katherine R. Gamble, a doctoral student in psychology at Georgetown University in Washington, DC. “This test, called the Triplets Learning Task (TLT), may provide some help for physicians who treat people with Parkinson’s disease, but we still have much work to do to better understand its utility,” she added.

The TLT tests implicit learning, which occurs without awareness or intent and relies on the caudate nucleus, an area of the brain affected by loss of dopamine. The test is a sequential learning task that does not require complex motor skills. In the TLT, participants see four open circles, and then two red dots appear. Patients are asked to respond when they see a green dot appear. Unknown to them, the location of the first red dot predicts the location of the green dot. Participants learn implicitly where the green dot will appear, and their responses become faster and more accurate.

Previous studies have shown that the caudate region in the brain underlies implicit learning. In the study, participants with Parkinson’s disease implicitly learned the dot pattern with training, but a loss of dopamine appears to negatively affect that learning. “Their performance began to decline toward the end of training, suggesting that people with Parkinson’s disease lack the neural resources in the caudate, such as dopamine, to complete the learning task,” said Ms. Gamble. The current study included 27 patients with Parkinson’s disease. The research team is now testing how implicit learning may differ by different stages of Parkinson’s disease and drug doses.

The Eyes May Help Diagnose Alzheimer’s Disease
The loss of a particular layer of retinal cells may reveal the presence of Alzheimer’s disease and provide a new way to track disease progression, according to an international team of researchers. The investigators examined retinas from the eyes of mice genetically engineered to develop Alzheimer’s disease.

“The retina is an extension of the brain, so it makes sense to see if the same pathologic processes found in an Alzheimer’s brain are also found in the eye,” said R. Scott Turner, MD, PhD, Director of the Memory Disorders Program at Georgetown University Medical Center in Washington, DC. “We know there’s an association between glaucoma and Alzheimer’s disease, in that both are characterized by loss of neurons, but the mechanisms are not clear.” Many researchers increasingly view glaucoma as a neurodegenerative disorder similar to Alzheimer’s disease, he added.

Most of the research to date examining the relationship between glaucoma and Alzheimer’s disease focused on the retinal ganglion cell layer, which transmits visual information via the optic nerve into the brain. Before that transmission happens, though, the retinal ganglion cells receive information from another layer in the retina—the inner nuclear layer.

The researchers examined the thickness of the retina, including the inner nuclear layer (which had not been studied previously in this setting) and the retinal ganglion cell layer. They found a significant loss of thickness in both layers. The inner nuclear layer had a 37% loss of neurons, and the retinal ganglion cell layer had a 49% loss of neurons, compared with healthy, age-matched control mice.

In humans, the structure and thickness of the retina can be readily measured using optical coherence tomography. This new tool is finding an increasing number of applications in research and clinical care, said Dr. Turner.

“This study suggests another path forward in understanding the disease process and could lead to new ways to diagnose or predict Alzheimer’s that could be as simple as looking into the eyes,” said Dr. Turner. “Parallel disease mechanisms suggest that new treatments developed for Alzheimer’s disease may also be useful for glaucoma.”

Research Suggests Warning Signs and Potential Treatments for MS
Recent research is increasing clinicians’ understanding of multiple sclerosis (MS) and may lead to new treatments and management strategies, said investigators. One study has shed light on the way in which antibodies in the bloodstream break through the blood–brain barrier to attack the optic nerves, spinal cord, and brain, causing the symptoms of neuromyelitis optica. Understanding how the antibodies bypass the blood–brain barrier could provide new approaches to treating the disease.

A protein involved in blood clotting might serve as an early biomarker for MS before symptoms occur, said Katerina Akassoglou, PhD, Professor in Residence of Neurology at the University of California, San Francisco School of Medicine. Early detection of the disease could lead to more effective early treatments.

In another study, low levels of a cholesterol protein correlated with the severity of MS. The finding suggests that the protein, which protects against inflammation, may protect against developing MS and may help regenerate damaged neurons, said Lidia Gardner, PhD, Assistant Professor of Neurology at the University of Tennessee in Memphis. Cholesterol drugs thus may be potential treatments for MS.

Researchers found that a type of immune system cell directly targets and damages nerve cell axons, just as MS does. This cell may be a target for new disease-modifying therapies. In addition, researchers have found that when exosomes—tiny, naturally occurring nanovesicles—are produced by dendritic cells and applied to the brain, they can deliver a mixture of proteins and RNAs that promote the regeneration of protective myelin sheaths and guard against MS symptoms.

Dot Test May Gauge the Progression of Dopamine Loss in Parkinson’s Disease
A simple dot test could help gauge the extent of dopamine loss in individuals with Parkinson’s disease, according to a pilot study by a multidisciplinary team of investigators. “It is difficult now to assess the extent of dopamine loss—a hallmark of Parkinson’s disease—in people with the disease,” said Katherine R. Gamble, a doctoral student in psychology at Georgetown University in Washington, DC. “This test, called the Triplets Learning Task (TLT), may provide some help for physicians who treat people with Parkinson’s disease, but we still have much work to do to better understand its utility,” she added.

The TLT tests implicit learning, which occurs without awareness or intent and relies on the caudate nucleus, an area of the brain affected by loss of dopamine. The test is a sequential learning task that does not require complex motor skills. In the TLT, participants see four open circles, and then two red dots appear. Patients are asked to respond when they see a green dot appear. Unknown to them, the location of the first red dot predicts the location of the green dot. Participants learn implicitly where the green dot will appear, and their responses become faster and more accurate.

Previous studies have shown that the caudate region in the brain underlies implicit learning. In the study, participants with Parkinson’s disease implicitly learned the dot pattern with training, but a loss of dopamine appears to negatively affect that learning. “Their performance began to decline toward the end of training, suggesting that people with Parkinson’s disease lack the neural resources in the caudate, such as dopamine, to complete the learning task,” said Ms. Gamble. The current study included 27 patients with Parkinson’s disease. The research team is now testing how implicit learning may differ by different stages of Parkinson’s disease and drug doses.

The Eyes May Help Diagnose Alzheimer’s Disease
The loss of a particular layer of retinal cells may reveal the presence of Alzheimer’s disease and provide a new way to track disease progression, according to an international team of researchers. The investigators examined retinas from the eyes of mice genetically engineered to develop Alzheimer’s disease.

“The retina is an extension of the brain, so it makes sense to see if the same pathologic processes found in an Alzheimer’s brain are also found in the eye,” said R. Scott Turner, MD, PhD, Director of the Memory Disorders Program at Georgetown University Medical Center in Washington, DC. “We know there’s an association between glaucoma and Alzheimer’s disease, in that both are characterized by loss of neurons, but the mechanisms are not clear.” Many researchers increasingly view glaucoma as a neurodegenerative disorder similar to Alzheimer’s disease, he added.

Most of the research to date examining the relationship between glaucoma and Alzheimer’s disease focused on the retinal ganglion cell layer, which transmits visual information via the optic nerve into the brain. Before that transmission happens, though, the retinal ganglion cells receive information from another layer in the retina—the inner nuclear layer.

The researchers examined the thickness of the retina, including the inner nuclear layer (which had not been studied previously in this setting) and the retinal ganglion cell layer. They found a significant loss of thickness in both layers. The inner nuclear layer had a 37% loss of neurons, and the retinal ganglion cell layer had a 49% loss of neurons, compared with healthy, age-matched control mice.

In humans, the structure and thickness of the retina can be readily measured using optical coherence tomography. This new tool is finding an increasing number of applications in research and clinical care, said Dr. Turner.

“This study suggests another path forward in understanding the disease process and could lead to new ways to diagnose or predict Alzheimer’s that could be as simple as looking into the eyes,” said Dr. Turner. “Parallel disease mechanisms suggest that new treatments developed for Alzheimer’s disease may also be useful for glaucoma.”

Research Suggests Warning Signs and Potential Treatments for MS
Recent research is increasing clinicians’ understanding of multiple sclerosis (MS) and may lead to new treatments and management strategies, said investigators. One study has shed light on the way in which antibodies in the bloodstream break through the blood–brain barrier to attack the optic nerves, spinal cord, and brain, causing the symptoms of neuromyelitis optica. Understanding how the antibodies bypass the blood–brain barrier could provide new approaches to treating the disease.

A protein involved in blood clotting might serve as an early biomarker for MS before symptoms occur, said Katerina Akassoglou, PhD, Professor in Residence of Neurology at the University of California, San Francisco School of Medicine. Early detection of the disease could lead to more effective early treatments.

In another study, low levels of a cholesterol protein correlated with the severity of MS. The finding suggests that the protein, which protects against inflammation, may protect against developing MS and may help regenerate damaged neurons, said Lidia Gardner, PhD, Assistant Professor of Neurology at the University of Tennessee in Memphis. Cholesterol drugs thus may be potential treatments for MS.

Researchers found that a type of immune system cell directly targets and damages nerve cell axons, just as MS does. This cell may be a target for new disease-modifying therapies. In addition, researchers have found that when exosomes—tiny, naturally occurring nanovesicles—are produced by dendritic cells and applied to the brain, they can deliver a mixture of proteins and RNAs that promote the regeneration of protective myelin sheaths and guard against MS symptoms.

SILVER SPRING, MD. – A Food and Drug Administration advisory panel agreed that phase III clinical trials of alemtuzumab for multiple sclerosis were unblinded and likely biased but still voted 12-6 that the manufacturer had provided substantial evidence that the immunomodulating drug was effective as a treatment for patients with relapsing forms of multiple sclerosis.

At a Nov. 13 meeting of the FDA’s Peripheral and Central Nervous System Advisory committee, the six panelists who voted no on this question did so because the studies were not well controlled. But the panelists who voted yes said that the drug clearly had some activity against multiple sclerosis (MS), had not been shown to be worse than the active comparator, and in treated patients had beneficial effects that were seen on MRIs, a more objective measure.

Despite an increased risk of serious side effects of treatment that included immune thrombocytopenia, the panel voted 17-0, with 1 abstention, that safety concerns did not preclude approval of the drug, when the potential benefits of the drug were considered. To address the serious risks of alemtuzumab, the manufacturer Genzyme has proposed a risk evaluation and mitigation strategy (REMS) that includes restricted distribution of the drug to physicians trained and certified in prescribing the drug, administration only in certified infusion centers, and close monitoring of patients for adverse events.

The panel was not asked specifically to recommend approval of the drug, which Genzyme has proposed be approved for treatment of patients with relapsing forms of multiple sclerosis. But panelists indicated in their comments that the drug could benefit some patients with MS – although not as a first-line treatment at this point.

Like other panelists who voted that the safety issues did not preclude approval, the panel chair, Dr. Nathan Fountain, professor of neurology at the University of Virginia, Charlottesville, said he would not want to deny the drug to patients severely affected by MS, who are well informed about the risks, with a stringent risk-management program in place. But, he added, "I don’t think this is appropriate at all for drug-naive, simple, uncomplicated relapsing-remitting patients after their first exacerbation."

Alemtuzumab is a monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Its exact mechanism on disease activity in patients with MS is not entirely clear, but is thought to be related to the depletion and repopulation of lymphocytes that occur after the drug is administered, according to Genzyme. The proposed dose is 12 mg/day in an intravenous infusion for 5 consecutive days, followed by the same dose for 3 consecutive days 1 year later.

In 2001, alemtuzumab was approved for treating B-cell chronic lymphocytic leukemia in the United States; it was approved in September 2013 for MS in the European Union. It is marketed as Campath in the United States, but if approved for MS, it will be marketed as Lemtrada.

In two phase III studies of patients with MS, who were treatment-naive or had failed a previous treatment, alemtuzumab (12 mg/day) administered in a series of IV infusions a year apart was compared with treatment with a subcutaneous injection of 44 mcg of interferon beta-1a (Rebif), approved in 2002 for treatment of relapsing forms of MS.

The rate of relapse (new neurologic symptoms or worsening of previous neurologic symptoms) over 2 years and sustained accumulation of disability over 6 months were the primary efficacy endpoints.

In the study of 581 recently diagnosed, untreated patients, the relapse rate over 2 years was 18% among those treated with alemtuzumab, compared with 39% among those on interferon beta-1a – a 55% reduction in the relapse rate that was statistically significant, according to the manufacturer. At the end of 2 years, 8% of those treated with alemtuzumab had experienced sustained disability, compared with 11% of those on interferon beta-1a, which was not statistically significant.

In the study of 840 MS patients who had experienced disease activity on another treatment, the relapse rate over 2 years was 26% among those on alemtuzumab, compared with 52% of those on interferon beta-1a, a 49% reduction in the relapse rate that was statistically significant. The risk of sustained disability over 2 years was almost 13% among those on alemtuzumab, compared with 21% among those on interferon beta-1a, a 42% reduction in risk that was statistically significant, according to Genzyme.

Major concerns raised by the FDA were elevated rates of serious adverse events in about 1,200 patients treated with alemtuzumab, which include serious thyroid-related adverse events (2.1%), immune thrombocytopenia (1.6%), autoimmune hemolytic anemia (0.2%), nephropathies (0.5%), acquired hemophilia A (0.1%), type 1 diabetes (0.2%), pneumonitis (0.5%), thyroid cancer (0.4%), melanoma (0.2%), and serious infusion reactions (2.6%). These adverse events cannot be prevented with close monitoring of patients or with preventive measures and can also occur years after the last dose is administered, the FDA reviewers pointed out.

Besides safety, the other major issue at the meeting was the disagreement between the FDA and Genzyme over the design of the clinical trials, which were open label, with clinicians and patients unblinded to the treatment. Dr. Billy Dunn, acting deputy director of the FDA’s division of neurology products, said that the FDA reviewers believed that bias was "pervasive" in these studies but that the impact the bias had on efficacy results was unclear.

There was a large difference in dropout rates between the treatment groups after randomization before the initiation of treatment between the two groups – almost 13% among those assigned to interferon beta-1a vs. 2% among those assigned to alemtuzumab in one of the studies. This could be explained by patients assigned to interferon beta-1a wanting the newer drug and was among the evidence FDA reviewers said illustrated the bias that was introduced into the studies because of unblinding.

In other questions posed by the FDA, most of the panel voted that the company had not provided substantial evidence that alemtuzumab had a beneficial on disability (14-2 with 2 abstentions) and that the two phase III studies were not adequate and well controlled (11-6 with 1 abstention).

Genzyme, a Sanofi company, is conducting an extension study of alemtuzumab in about 1,300 patients (including those in the three studies) that is evaluating safety and efficacy for up to 5 years, which includes patients now being treated in Europe.

A decision on approval is expected in December. The FDA usually follows the recommendations of its advisory panels. Members have been cleared of potential conflicts; occasionally, a panelist is given a waiver for a potential conflict, but not at this meeting.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – A Food and Drug Administration advisory panel agreed that phase III clinical trials of alemtuzumab for multiple sclerosis were unblinded and likely biased but still voted 12-6 that the manufacturer had provided substantial evidence that the immunomodulating drug was effective as a treatment for patients with relapsing forms of multiple sclerosis.

At a Nov. 13 meeting of the FDA’s Peripheral and Central Nervous System Advisory committee, the six panelists who voted no on this question did so because the studies were not well controlled. But the panelists who voted yes said that the drug clearly had some activity against multiple sclerosis (MS), had not been shown to be worse than the active comparator, and in treated patients had beneficial effects that were seen on MRIs, a more objective measure.

Despite an increased risk of serious side effects of treatment that included immune thrombocytopenia, the panel voted 17-0, with 1 abstention, that safety concerns did not preclude approval of the drug, when the potential benefits of the drug were considered. To address the serious risks of alemtuzumab, the manufacturer Genzyme has proposed a risk evaluation and mitigation strategy (REMS) that includes restricted distribution of the drug to physicians trained and certified in prescribing the drug, administration only in certified infusion centers, and close monitoring of patients for adverse events.

The panel was not asked specifically to recommend approval of the drug, which Genzyme has proposed be approved for treatment of patients with relapsing forms of multiple sclerosis. But panelists indicated in their comments that the drug could benefit some patients with MS – although not as a first-line treatment at this point.

Like other panelists who voted that the safety issues did not preclude approval, the panel chair, Dr. Nathan Fountain, professor of neurology at the University of Virginia, Charlottesville, said he would not want to deny the drug to patients severely affected by MS, who are well informed about the risks, with a stringent risk-management program in place. But, he added, "I don’t think this is appropriate at all for drug-naive, simple, uncomplicated relapsing-remitting patients after their first exacerbation."

Alemtuzumab is a monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Its exact mechanism on disease activity in patients with MS is not entirely clear, but is thought to be related to the depletion and repopulation of lymphocytes that occur after the drug is administered, according to Genzyme. The proposed dose is 12 mg/day in an intravenous infusion for 5 consecutive days, followed by the same dose for 3 consecutive days 1 year later.

In 2001, alemtuzumab was approved for treating B-cell chronic lymphocytic leukemia in the United States; it was approved in September 2013 for MS in the European Union. It is marketed as Campath in the United States, but if approved for MS, it will be marketed as Lemtrada.

In two phase III studies of patients with MS, who were treatment-naive or had failed a previous treatment, alemtuzumab (12 mg/day) administered in a series of IV infusions a year apart was compared with treatment with a subcutaneous injection of 44 mcg of interferon beta-1a (Rebif), approved in 2002 for treatment of relapsing forms of MS.

The rate of relapse (new neurologic symptoms or worsening of previous neurologic symptoms) over 2 years and sustained accumulation of disability over 6 months were the primary efficacy endpoints.

In the study of 581 recently diagnosed, untreated patients, the relapse rate over 2 years was 18% among those treated with alemtuzumab, compared with 39% among those on interferon beta-1a – a 55% reduction in the relapse rate that was statistically significant, according to the manufacturer. At the end of 2 years, 8% of those treated with alemtuzumab had experienced sustained disability, compared with 11% of those on interferon beta-1a, which was not statistically significant.

In the study of 840 MS patients who had experienced disease activity on another treatment, the relapse rate over 2 years was 26% among those on alemtuzumab, compared with 52% of those on interferon beta-1a, a 49% reduction in the relapse rate that was statistically significant. The risk of sustained disability over 2 years was almost 13% among those on alemtuzumab, compared with 21% among those on interferon beta-1a, a 42% reduction in risk that was statistically significant, according to Genzyme.

Major concerns raised by the FDA were elevated rates of serious adverse events in about 1,200 patients treated with alemtuzumab, which include serious thyroid-related adverse events (2.1%), immune thrombocytopenia (1.6%), autoimmune hemolytic anemia (0.2%), nephropathies (0.5%), acquired hemophilia A (0.1%), type 1 diabetes (0.2%), pneumonitis (0.5%), thyroid cancer (0.4%), melanoma (0.2%), and serious infusion reactions (2.6%). These adverse events cannot be prevented with close monitoring of patients or with preventive measures and can also occur years after the last dose is administered, the FDA reviewers pointed out.

Besides safety, the other major issue at the meeting was the disagreement between the FDA and Genzyme over the design of the clinical trials, which were open label, with clinicians and patients unblinded to the treatment. Dr. Billy Dunn, acting deputy director of the FDA’s division of neurology products, said that the FDA reviewers believed that bias was "pervasive" in these studies but that the impact the bias had on efficacy results was unclear.

There was a large difference in dropout rates between the treatment groups after randomization before the initiation of treatment between the two groups – almost 13% among those assigned to interferon beta-1a vs. 2% among those assigned to alemtuzumab in one of the studies. This could be explained by patients assigned to interferon beta-1a wanting the newer drug and was among the evidence FDA reviewers said illustrated the bias that was introduced into the studies because of unblinding.

In other questions posed by the FDA, most of the panel voted that the company had not provided substantial evidence that alemtuzumab had a beneficial on disability (14-2 with 2 abstentions) and that the two phase III studies were not adequate and well controlled (11-6 with 1 abstention).

Genzyme, a Sanofi company, is conducting an extension study of alemtuzumab in about 1,300 patients (including those in the three studies) that is evaluating safety and efficacy for up to 5 years, which includes patients now being treated in Europe.

A decision on approval is expected in December. The FDA usually follows the recommendations of its advisory panels. Members have been cleared of potential conflicts; occasionally, a panelist is given a waiver for a potential conflict, but not at this meeting.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – A Food and Drug Administration advisory panel agreed that phase III clinical trials of alemtuzumab for multiple sclerosis were unblinded and likely biased but still voted 12-6 that the manufacturer had provided substantial evidence that the immunomodulating drug was effective as a treatment for patients with relapsing forms of multiple sclerosis.

At a Nov. 13 meeting of the FDA’s Peripheral and Central Nervous System Advisory committee, the six panelists who voted no on this question did so because the studies were not well controlled. But the panelists who voted yes said that the drug clearly had some activity against multiple sclerosis (MS), had not been shown to be worse than the active comparator, and in treated patients had beneficial effects that were seen on MRIs, a more objective measure.

Despite an increased risk of serious side effects of treatment that included immune thrombocytopenia, the panel voted 17-0, with 1 abstention, that safety concerns did not preclude approval of the drug, when the potential benefits of the drug were considered. To address the serious risks of alemtuzumab, the manufacturer Genzyme has proposed a risk evaluation and mitigation strategy (REMS) that includes restricted distribution of the drug to physicians trained and certified in prescribing the drug, administration only in certified infusion centers, and close monitoring of patients for adverse events.

The panel was not asked specifically to recommend approval of the drug, which Genzyme has proposed be approved for treatment of patients with relapsing forms of multiple sclerosis. But panelists indicated in their comments that the drug could benefit some patients with MS – although not as a first-line treatment at this point.

Like other panelists who voted that the safety issues did not preclude approval, the panel chair, Dr. Nathan Fountain, professor of neurology at the University of Virginia, Charlottesville, said he would not want to deny the drug to patients severely affected by MS, who are well informed about the risks, with a stringent risk-management program in place. But, he added, "I don’t think this is appropriate at all for drug-naive, simple, uncomplicated relapsing-remitting patients after their first exacerbation."

Alemtuzumab is a monoclonal antibody that binds to the CD52 antigen present at high levels on the surface of T and B lymphocytes. Its exact mechanism on disease activity in patients with MS is not entirely clear, but is thought to be related to the depletion and repopulation of lymphocytes that occur after the drug is administered, according to Genzyme. The proposed dose is 12 mg/day in an intravenous infusion for 5 consecutive days, followed by the same dose for 3 consecutive days 1 year later.

In 2001, alemtuzumab was approved for treating B-cell chronic lymphocytic leukemia in the United States; it was approved in September 2013 for MS in the European Union. It is marketed as Campath in the United States, but if approved for MS, it will be marketed as Lemtrada.

In two phase III studies of patients with MS, who were treatment-naive or had failed a previous treatment, alemtuzumab (12 mg/day) administered in a series of IV infusions a year apart was compared with treatment with a subcutaneous injection of 44 mcg of interferon beta-1a (Rebif), approved in 2002 for treatment of relapsing forms of MS.

The rate of relapse (new neurologic symptoms or worsening of previous neurologic symptoms) over 2 years and sustained accumulation of disability over 6 months were the primary efficacy endpoints.

In the study of 581 recently diagnosed, untreated patients, the relapse rate over 2 years was 18% among those treated with alemtuzumab, compared with 39% among those on interferon beta-1a – a 55% reduction in the relapse rate that was statistically significant, according to the manufacturer. At the end of 2 years, 8% of those treated with alemtuzumab had experienced sustained disability, compared with 11% of those on interferon beta-1a, which was not statistically significant.

In the study of 840 MS patients who had experienced disease activity on another treatment, the relapse rate over 2 years was 26% among those on alemtuzumab, compared with 52% of those on interferon beta-1a, a 49% reduction in the relapse rate that was statistically significant. The risk of sustained disability over 2 years was almost 13% among those on alemtuzumab, compared with 21% among those on interferon beta-1a, a 42% reduction in risk that was statistically significant, according to Genzyme.

Major concerns raised by the FDA were elevated rates of serious adverse events in about 1,200 patients treated with alemtuzumab, which include serious thyroid-related adverse events (2.1%), immune thrombocytopenia (1.6%), autoimmune hemolytic anemia (0.2%), nephropathies (0.5%), acquired hemophilia A (0.1%), type 1 diabetes (0.2%), pneumonitis (0.5%), thyroid cancer (0.4%), melanoma (0.2%), and serious infusion reactions (2.6%). These adverse events cannot be prevented with close monitoring of patients or with preventive measures and can also occur years after the last dose is administered, the FDA reviewers pointed out.

Besides safety, the other major issue at the meeting was the disagreement between the FDA and Genzyme over the design of the clinical trials, which were open label, with clinicians and patients unblinded to the treatment. Dr. Billy Dunn, acting deputy director of the FDA’s division of neurology products, said that the FDA reviewers believed that bias was "pervasive" in these studies but that the impact the bias had on efficacy results was unclear.

There was a large difference in dropout rates between the treatment groups after randomization before the initiation of treatment between the two groups – almost 13% among those assigned to interferon beta-1a vs. 2% among those assigned to alemtuzumab in one of the studies. This could be explained by patients assigned to interferon beta-1a wanting the newer drug and was among the evidence FDA reviewers said illustrated the bias that was introduced into the studies because of unblinding.

In other questions posed by the FDA, most of the panel voted that the company had not provided substantial evidence that alemtuzumab had a beneficial on disability (14-2 with 2 abstentions) and that the two phase III studies were not adequate and well controlled (11-6 with 1 abstention).

Genzyme, a Sanofi company, is conducting an extension study of alemtuzumab in about 1,300 patients (including those in the three studies) that is evaluating safety and efficacy for up to 5 years, which includes patients now being treated in Europe.

A decision on approval is expected in December. The FDA usually follows the recommendations of its advisory panels. Members have been cleared of potential conflicts; occasionally, a panelist is given a waiver for a potential conflict, but not at this meeting.

emechcatie@frontlinemedcom.com

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

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

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

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

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

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

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

—Erik Greb
Senior Associate Editor

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

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

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

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

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

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

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

—Erik Greb
Senior Associate Editor

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

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

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

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

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

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

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

—Erik Greb
Senior Associate Editor

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

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

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

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

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

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

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

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

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

—Erik Greb
Senior Associate Editor

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

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

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

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

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

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

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

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

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

—Erik Greb
Senior Associate Editor

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

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

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

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

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

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

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

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

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

—Erik Greb
Senior Associate Editor