Multiple Sclerosis

TORONTO — The National Multiple Sclerosis Society is assuming a leadership role in disseminating information and mobilizing research on the role of chronic cerebrospinal venous insufficiency in the etiology and treatment of multiple sclerosis. The move comes in response to mounting pressure from patients and the scientific community questioning the hypothesis.

The society and the American Academy of Neurology jointly organized a Web forum during the annual meeting of the AAN that was open to thousands of off-site patients, family members, researchers, and members of the press.

The forum featured two of the investigators whose research on chronic cerebrospinal venous insufficiency (CCSVI) has sparked so much interest. In addition, the society has implemented an expedited research program to see whether scientific results can be replicated and further avenues explored.

“I know the MS Society shares the public's sense of urgency in advancing any lead that may help us understand the cause, provide the cure, or change the course of MS,” said Dr. Aaron E. Miller, the society's chief medical officer. Dr. Miller, who is also professor of neurology and director of the MS Center at the Mount Sinai School of Medicine, New York, participated in the forum.

“The MS Society suggested holding a cosponsored educational Web forum on the CCSVI and MS … because of the extent of misinformation and general confusion we were observing both on the Internet and in the media. We also felt the timing to be apropos because of the number of experts who would be [at the AAN meeting],” Arney Rosenblat, the society's vice president of public affairs, said in an interview.

More than 5,000 people were preregistered for the forum, and more than 1,000 questions were submitted.

The speakers included Dr. Paolo Zamboni, director of the Vascular Diseases Center at the University of Ferrara, Italy, whose team was instrumental in hypothesizing a link between cerebrovascular insufficiency and MS.

In June last year, he and his colleagues described evidence of slowed and obstructed drainage in cerebrospinal veins in 100% of patients with MS, a condition that they called CCSVI (J. Neurol. Neurosurg. Psychiatry 2009;80:392–9). They also suggested that blood flow is detoured around obstructions and that reversed blood flow might initiate the inflammation and immune-mediated brain damage characteristic of MS.

The investigators had used advanced ultrasound techniques to evaluate blood outflow in 65 people with MS and in 235 controls who were either healthy or had other neurologic disorders.

Later last year, in December, the group reported on the safety and preliminary outcomes of surgical intervention using percutaneous transluminal angioplasty in 35 patients with relapsing-remitting, secondary progressive, and primary progressive multiple sclerosis (J. Vasc. Surg. 2009;50:1348–58).

Some positive effects were described—significant reduction of relapses and active lesions, improved function and quality of life, and less fatigue—although a high rate of restenosis was reported. The group issued a call for larger, controlled trials.

Dr. Robert Zivadinov, director of the Buffalo (N.Y.) Neuroimaging Analysis Center, was another featured speaker. He and his group are exploring the prevalence of venous obstruction in 1,700 children and adults with MS, healthy controls, autoimmune-vascular disorders, and other neurologic diseases using a combination of transcranial and extracranial venous Doppler methods.

They released their preliminary results earlier this year, and Dr. Zivadinov unveiled the results of phase I of the Combined Transcranial and Extracranial Venous Doppler Evaluation Study during the forum. In these first 500 patients, 62.5% of MS patients met CCSVI diagnostic criteria, compared with 25.5% of healthy controls and 45.8% of those with other neurologic diseases. Although there was an increased likelihood that MS patients would meet the criteria for CCSVI (odds ratio, 4.85; P less than 0.001), compared with healthy controls, CCSVI seemed to be present in a proportion of healthy controls as well—in contradiction to Dr. Zamboni's hypothesis.

By late 2009, patients and their families began asking for more information about CCSVI as a possible cause of MS, and endovascular stent treatment as a possible cure. At Stanford (Calif.) University, vascular specialist Dr. Michael D. Dake embarked on a program to insert stents into the internal jugular veins of MS patients based on Dr. Zamboni's reports—a program that was terminated in December because the procedure was deemed experimental.

Complications included the death of one of Dr. Dake's patients who had been on coumadin and a dislodged stent that required surgical removal in another patient.

With research reports published in reputable medical publications and calls from patients for more information, the MS Society decided to take an active role in evaluating “this interesting hypothesis that needed to be further explored: whether there is an association between CCSVI and MS,” said Patricia A. O'Looney, Ph.D., the vice president of biomedical research for the society.

She cited previous research programs in gender differences in MS, genetics, and myelin repair mechanisms, as examples of the society's role in encouraging research in “underexplored” areas.

On Dec. 16, 2009, the society invited researchers worldwide to submit applications for funding and proposals for further research on CCSVI in MS. The deadline for submissions was Feb. 9, and decisions are expected mid-June.

In an interview, Dr. O'Looney declined to specify how much money has been allocated by the society. She said that she expects more than one project to be funded and that the hope is that definitive information about the CCSVI-MS association would be available within 2 years.

“We felt that answering this question was critical before patients underwent interventional treatment, which carries its own risks,” Dr. O'Looney said.

Dr. Zivadinov (left), Dr. Miller (third from left), and Dr. Zamboni (standing) discuss CCSVI in a forum held at the AAN meeting.

Source Courtesy National MS Society

TORONTO — The National Multiple Sclerosis Society is assuming a leadership role in disseminating information and mobilizing research on the role of chronic cerebrospinal venous insufficiency in the etiology and treatment of multiple sclerosis. The move comes in response to mounting pressure from patients and the scientific community questioning the hypothesis.

The society and the American Academy of Neurology jointly organized a Web forum during the annual meeting of the AAN that was open to thousands of off-site patients, family members, researchers, and members of the press.

The forum featured two of the investigators whose research on chronic cerebrospinal venous insufficiency (CCSVI) has sparked so much interest. In addition, the society has implemented an expedited research program to see whether scientific results can be replicated and further avenues explored.

“I know the MS Society shares the public's sense of urgency in advancing any lead that may help us understand the cause, provide the cure, or change the course of MS,” said Dr. Aaron E. Miller, the society's chief medical officer. Dr. Miller, who is also professor of neurology and director of the MS Center at the Mount Sinai School of Medicine, New York, participated in the forum.

“The MS Society suggested holding a cosponsored educational Web forum on the CCSVI and MS … because of the extent of misinformation and general confusion we were observing both on the Internet and in the media. We also felt the timing to be apropos because of the number of experts who would be [at the AAN meeting],” Arney Rosenblat, the society's vice president of public affairs, said in an interview.

More than 5,000 people were preregistered for the forum, and more than 1,000 questions were submitted.

The speakers included Dr. Paolo Zamboni, director of the Vascular Diseases Center at the University of Ferrara, Italy, whose team was instrumental in hypothesizing a link between cerebrovascular insufficiency and MS.

In June last year, he and his colleagues described evidence of slowed and obstructed drainage in cerebrospinal veins in 100% of patients with MS, a condition that they called CCSVI (J. Neurol. Neurosurg. Psychiatry 2009;80:392–9). They also suggested that blood flow is detoured around obstructions and that reversed blood flow might initiate the inflammation and immune-mediated brain damage characteristic of MS.

The investigators had used advanced ultrasound techniques to evaluate blood outflow in 65 people with MS and in 235 controls who were either healthy or had other neurologic disorders.

Later last year, in December, the group reported on the safety and preliminary outcomes of surgical intervention using percutaneous transluminal angioplasty in 35 patients with relapsing-remitting, secondary progressive, and primary progressive multiple sclerosis (J. Vasc. Surg. 2009;50:1348–58).

Some positive effects were described—significant reduction of relapses and active lesions, improved function and quality of life, and less fatigue—although a high rate of restenosis was reported. The group issued a call for larger, controlled trials.

Dr. Robert Zivadinov, director of the Buffalo (N.Y.) Neuroimaging Analysis Center, was another featured speaker. He and his group are exploring the prevalence of venous obstruction in 1,700 children and adults with MS, healthy controls, autoimmune-vascular disorders, and other neurologic diseases using a combination of transcranial and extracranial venous Doppler methods.

They released their preliminary results earlier this year, and Dr. Zivadinov unveiled the results of phase I of the Combined Transcranial and Extracranial Venous Doppler Evaluation Study during the forum. In these first 500 patients, 62.5% of MS patients met CCSVI diagnostic criteria, compared with 25.5% of healthy controls and 45.8% of those with other neurologic diseases. Although there was an increased likelihood that MS patients would meet the criteria for CCSVI (odds ratio, 4.85; P less than 0.001), compared with healthy controls, CCSVI seemed to be present in a proportion of healthy controls as well—in contradiction to Dr. Zamboni's hypothesis.

By late 2009, patients and their families began asking for more information about CCSVI as a possible cause of MS, and endovascular stent treatment as a possible cure. At Stanford (Calif.) University, vascular specialist Dr. Michael D. Dake embarked on a program to insert stents into the internal jugular veins of MS patients based on Dr. Zamboni's reports—a program that was terminated in December because the procedure was deemed experimental.

Complications included the death of one of Dr. Dake's patients who had been on coumadin and a dislodged stent that required surgical removal in another patient.

With research reports published in reputable medical publications and calls from patients for more information, the MS Society decided to take an active role in evaluating “this interesting hypothesis that needed to be further explored: whether there is an association between CCSVI and MS,” said Patricia A. O'Looney, Ph.D., the vice president of biomedical research for the society.

She cited previous research programs in gender differences in MS, genetics, and myelin repair mechanisms, as examples of the society's role in encouraging research in “underexplored” areas.

On Dec. 16, 2009, the society invited researchers worldwide to submit applications for funding and proposals for further research on CCSVI in MS. The deadline for submissions was Feb. 9, and decisions are expected mid-June.

In an interview, Dr. O'Looney declined to specify how much money has been allocated by the society. She said that she expects more than one project to be funded and that the hope is that definitive information about the CCSVI-MS association would be available within 2 years.

“We felt that answering this question was critical before patients underwent interventional treatment, which carries its own risks,” Dr. O'Looney said.

Dr. Zivadinov (left), Dr. Miller (third from left), and Dr. Zamboni (standing) discuss CCSVI in a forum held at the AAN meeting.

Source Courtesy National MS Society

TORONTO — The National Multiple Sclerosis Society is assuming a leadership role in disseminating information and mobilizing research on the role of chronic cerebrospinal venous insufficiency in the etiology and treatment of multiple sclerosis. The move comes in response to mounting pressure from patients and the scientific community questioning the hypothesis.

The society and the American Academy of Neurology jointly organized a Web forum during the annual meeting of the AAN that was open to thousands of off-site patients, family members, researchers, and members of the press.

The forum featured two of the investigators whose research on chronic cerebrospinal venous insufficiency (CCSVI) has sparked so much interest. In addition, the society has implemented an expedited research program to see whether scientific results can be replicated and further avenues explored.

“I know the MS Society shares the public's sense of urgency in advancing any lead that may help us understand the cause, provide the cure, or change the course of MS,” said Dr. Aaron E. Miller, the society's chief medical officer. Dr. Miller, who is also professor of neurology and director of the MS Center at the Mount Sinai School of Medicine, New York, participated in the forum.

“The MS Society suggested holding a cosponsored educational Web forum on the CCSVI and MS … because of the extent of misinformation and general confusion we were observing both on the Internet and in the media. We also felt the timing to be apropos because of the number of experts who would be [at the AAN meeting],” Arney Rosenblat, the society's vice president of public affairs, said in an interview.

More than 5,000 people were preregistered for the forum, and more than 1,000 questions were submitted.

The speakers included Dr. Paolo Zamboni, director of the Vascular Diseases Center at the University of Ferrara, Italy, whose team was instrumental in hypothesizing a link between cerebrovascular insufficiency and MS.

In June last year, he and his colleagues described evidence of slowed and obstructed drainage in cerebrospinal veins in 100% of patients with MS, a condition that they called CCSVI (J. Neurol. Neurosurg. Psychiatry 2009;80:392–9). They also suggested that blood flow is detoured around obstructions and that reversed blood flow might initiate the inflammation and immune-mediated brain damage characteristic of MS.

The investigators had used advanced ultrasound techniques to evaluate blood outflow in 65 people with MS and in 235 controls who were either healthy or had other neurologic disorders.

Later last year, in December, the group reported on the safety and preliminary outcomes of surgical intervention using percutaneous transluminal angioplasty in 35 patients with relapsing-remitting, secondary progressive, and primary progressive multiple sclerosis (J. Vasc. Surg. 2009;50:1348–58).

Some positive effects were described—significant reduction of relapses and active lesions, improved function and quality of life, and less fatigue—although a high rate of restenosis was reported. The group issued a call for larger, controlled trials.

Dr. Robert Zivadinov, director of the Buffalo (N.Y.) Neuroimaging Analysis Center, was another featured speaker. He and his group are exploring the prevalence of venous obstruction in 1,700 children and adults with MS, healthy controls, autoimmune-vascular disorders, and other neurologic diseases using a combination of transcranial and extracranial venous Doppler methods.

They released their preliminary results earlier this year, and Dr. Zivadinov unveiled the results of phase I of the Combined Transcranial and Extracranial Venous Doppler Evaluation Study during the forum. In these first 500 patients, 62.5% of MS patients met CCSVI diagnostic criteria, compared with 25.5% of healthy controls and 45.8% of those with other neurologic diseases. Although there was an increased likelihood that MS patients would meet the criteria for CCSVI (odds ratio, 4.85; P less than 0.001), compared with healthy controls, CCSVI seemed to be present in a proportion of healthy controls as well—in contradiction to Dr. Zamboni's hypothesis.

By late 2009, patients and their families began asking for more information about CCSVI as a possible cause of MS, and endovascular stent treatment as a possible cure. At Stanford (Calif.) University, vascular specialist Dr. Michael D. Dake embarked on a program to insert stents into the internal jugular veins of MS patients based on Dr. Zamboni's reports—a program that was terminated in December because the procedure was deemed experimental.

Complications included the death of one of Dr. Dake's patients who had been on coumadin and a dislodged stent that required surgical removal in another patient.

With research reports published in reputable medical publications and calls from patients for more information, the MS Society decided to take an active role in evaluating “this interesting hypothesis that needed to be further explored: whether there is an association between CCSVI and MS,” said Patricia A. O'Looney, Ph.D., the vice president of biomedical research for the society.

She cited previous research programs in gender differences in MS, genetics, and myelin repair mechanisms, as examples of the society's role in encouraging research in “underexplored” areas.

On Dec. 16, 2009, the society invited researchers worldwide to submit applications for funding and proposals for further research on CCSVI in MS. The deadline for submissions was Feb. 9, and decisions are expected mid-June.

In an interview, Dr. O'Looney declined to specify how much money has been allocated by the society. She said that she expects more than one project to be funded and that the hope is that definitive information about the CCSVI-MS association would be available within 2 years.

“We felt that answering this question was critical before patients underwent interventional treatment, which carries its own risks,” Dr. O'Looney said.

Dr. Zivadinov (left), Dr. Miller (third from left), and Dr. Zamboni (standing) discuss CCSVI in a forum held at the AAN meeting.

Source Courtesy National MS Society

Neutralizing antibodies to interferon beta not only persist in some multiple sclerosis patients who discontinue the recombinant-DNA treatment, they also appear to worsen the disease course.

In patients with relapsing-remitting MS who had been treated with interferon beta in the past, the relapse rate was higher and progression of disability faster in those who had neutralizing antibodies in their circulation than in those who did not have the antibodies, said Dr. Laura F. van der Voort of Vrije University Medical Center, Amsterdam, and associates.

They reviewed the medical records of 71 MS patients treated with interferon beta between 1994 and 2006. A median of 25 months after discontinuing therapy, 17 patients (24%) still had circulating neutralizing antibodies to interferon beta.

Patients with persistent antibodies were no different from those without them, even when considering potential predisposing factors such as age at MS onset, sex, MS subtype, disease duration, duration of interferon-beta therapy, and degree of disability at the start of treatment. The relapse rate was nearly 5 times higher in antibody-positive patients than in antibody-negative patients (Arch. Neurol. 2010; Feb. 8 [doi:10.1001/archneurol.2010.21

Patients with persistent neutralizing antibodies also showed faster progression of disability when evaluated using the Expanded Disability Status Scale.

“Most patients who discontinued interferon beta treatment because of perceived efficacy failure were not neutralizing-antibody positive,” the authors wrote. It is not yet clear why neutralizing antibodies to interferon beta can persist months or years after exposure to the antigen has ceased or how persisting antibodies exert their effect on MS activity.

It is possible that the antibodies affect endogenous interferon pathways, causing “a more proinflammatory modification of the immune system. Alternatively, the tendency to develop and sustain anti–interferon beta antibodies might be a reflection of a more active immune system.”

The retrospective nature and the small sample of the study did not allow for definitive conclusions to be drawn, and causality could not be proven, they added.

This study was supported in part by a targeted research project on neutralizing antibodies funded by the European Commission. Dr. van der Voort reported being involved in clinical trials of companies that market drugs for MS, and working with some that have development programs for future drugs for the disease.

Neutralizing antibodies to interferon beta not only persist in some multiple sclerosis patients who discontinue the recombinant-DNA treatment, they also appear to worsen the disease course.

In patients with relapsing-remitting MS who had been treated with interferon beta in the past, the relapse rate was higher and progression of disability faster in those who had neutralizing antibodies in their circulation than in those who did not have the antibodies, said Dr. Laura F. van der Voort of Vrije University Medical Center, Amsterdam, and associates.

They reviewed the medical records of 71 MS patients treated with interferon beta between 1994 and 2006. A median of 25 months after discontinuing therapy, 17 patients (24%) still had circulating neutralizing antibodies to interferon beta.

Patients with persistent antibodies were no different from those without them, even when considering potential predisposing factors such as age at MS onset, sex, MS subtype, disease duration, duration of interferon-beta therapy, and degree of disability at the start of treatment. The relapse rate was nearly 5 times higher in antibody-positive patients than in antibody-negative patients (Arch. Neurol. 2010; Feb. 8 [doi:10.1001/archneurol.2010.21

Patients with persistent neutralizing antibodies also showed faster progression of disability when evaluated using the Expanded Disability Status Scale.

“Most patients who discontinued interferon beta treatment because of perceived efficacy failure were not neutralizing-antibody positive,” the authors wrote. It is not yet clear why neutralizing antibodies to interferon beta can persist months or years after exposure to the antigen has ceased or how persisting antibodies exert their effect on MS activity.

It is possible that the antibodies affect endogenous interferon pathways, causing “a more proinflammatory modification of the immune system. Alternatively, the tendency to develop and sustain anti–interferon beta antibodies might be a reflection of a more active immune system.”

The retrospective nature and the small sample of the study did not allow for definitive conclusions to be drawn, and causality could not be proven, they added.

This study was supported in part by a targeted research project on neutralizing antibodies funded by the European Commission. Dr. van der Voort reported being involved in clinical trials of companies that market drugs for MS, and working with some that have development programs for future drugs for the disease.

Neutralizing antibodies to interferon beta not only persist in some multiple sclerosis patients who discontinue the recombinant-DNA treatment, they also appear to worsen the disease course.

In patients with relapsing-remitting MS who had been treated with interferon beta in the past, the relapse rate was higher and progression of disability faster in those who had neutralizing antibodies in their circulation than in those who did not have the antibodies, said Dr. Laura F. van der Voort of Vrije University Medical Center, Amsterdam, and associates.

They reviewed the medical records of 71 MS patients treated with interferon beta between 1994 and 2006. A median of 25 months after discontinuing therapy, 17 patients (24%) still had circulating neutralizing antibodies to interferon beta.

Patients with persistent antibodies were no different from those without them, even when considering potential predisposing factors such as age at MS onset, sex, MS subtype, disease duration, duration of interferon-beta therapy, and degree of disability at the start of treatment. The relapse rate was nearly 5 times higher in antibody-positive patients than in antibody-negative patients (Arch. Neurol. 2010; Feb. 8 [doi:10.1001/archneurol.2010.21

Patients with persistent neutralizing antibodies also showed faster progression of disability when evaluated using the Expanded Disability Status Scale.

“Most patients who discontinued interferon beta treatment because of perceived efficacy failure were not neutralizing-antibody positive,” the authors wrote. It is not yet clear why neutralizing antibodies to interferon beta can persist months or years after exposure to the antigen has ceased or how persisting antibodies exert their effect on MS activity.

It is possible that the antibodies affect endogenous interferon pathways, causing “a more proinflammatory modification of the immune system. Alternatively, the tendency to develop and sustain anti–interferon beta antibodies might be a reflection of a more active immune system.”

The retrospective nature and the small sample of the study did not allow for definitive conclusions to be drawn, and causality could not be proven, they added.

This study was supported in part by a targeted research project on neutralizing antibodies funded by the European Commission. Dr. van der Voort reported being involved in clinical trials of companies that market drugs for MS, and working with some that have development programs for future drugs for the disease.

Major Finding: Patients taking 2 mg/kg of daclizumab every 2 weeks plus interferon beta had significantly fewer new or enlarged gadolinium-enhancing lesions after 24 weeks of treatment than did those taking interferon beta plus placebo (1.32 vs. 4.75).

Data Source: CHOICE study: Double-blind, randomized, placebo-controlled, phase II trial of 230 patients with active relapsing MS

Disclosures: Many investigators reported potential conflicts of interest with Biogen Idec Inc., maker of the MS medications, Tysabri and Avonex. Some of the investigators are employed by and own stock with either Biogen Idec or Facet Biotech Corp., both of which funded the trial. Dr. Greenberg and Dr. Stüve disclosed potential conflicts of interest with several manufacturers of MS drugs.

Multiple sclerosis patients who experience relapsing disease while taking interferon beta might be able to reduce their number of new or enlarging lesions by adding the humanized monoclonal antibody daclizumab.

Besides reducing the risk of lesion growth and formation, the antibody might exert at least part of its effects through a mechanism that is now suggested by several lines of evidence to be a potential drug target and an important part of further understanding the pathogenesis of the disease, Dr. Daniel Wynn of Consultants in Neurology Multiple Sclerosis Center, Northbrook, Ill., and his associates reported (Lancet Neurol. 2010 Feb. 16 [doi:10.1016/S1474-4422(10)70033-8

Daclizumab (Zenapax) has been already approved by the Food and Drug Administration for the prophylaxis of acute organ rejection in patients receiving renal transplants.

“The true effects of this trial and previous observations on daclizumab might be more far-reaching than they seem at first glance,” Dr. Olaf Stüve and Dr. Benjamin M. Greenberg wrote in an editorial (Lancet Neurol. 2010 Feb. 16 [doi:10.1016/S1474-4422(10)70032-6

Daclizumab was thought to inhibit T-cell proliferation and activation by binding to the CD25 subunit of the human high-affinity interleukin-2 receptor, but in this and other studies of MS patients treated with daclizumab, T cells have shown normal proliferative and activation responses.

Rather than reduce the activation or proliferation of T cells, Dr. Wynn and his colleagues found that the reduction of disease activity with daclizumab appears to be associated with an expansion of a regulatory subset of CD56

In the 51-center CHOICE study, the investigators randomized 75 patients to daclizumab 2 mg/kg every 2 weeks, 78 patients to daclizumab 1 mg/kg every 4 weeks, and 77 patients to placebo. These patients had a mean age of about 40 years and continued to take their baseline interferon beta regimens. Patients in each treatment arm averaged about 2.5 relapses in the previous 2 years and had a mean Expanded Disability Status Scale score of 3 (0 = normal; 10 = death). All of the patients had experienced at least one relapse or at least one gadolinium-enhancing brain or spinal cord lesion in the previous year while on a stable interferon beta regimen.

No significant differences were noted between the low-dose daclizumab and placebo groups on any of the imaging or clinical end points.

However, at 24 weeks, significantly fewer new or enlarged gadolinium-enhancing lesions had developed in the high-dose daclizumab group, compared with the placebo-treated group (mean of 1.32 lesions vs. 4.75, respectively). Enlarged lesions were defined by at least a 50% increase in size for lesions measuring at least 5 mm in diameter and by at least a 20% increase in size for lesions less than 5 mm.

High-dose daclizumab also was associated with a significantly lower number of new gadolinium-enhancing lesions alone, compared with placebo (mean of 1.18 vs. 3.95).

By 24 weeks, the high-dose daclizumab patients developed significantly fewer T2 lesions than did placebo-treated patients (1.1 vs. 3.4).

None of the groups were significantly different in terms of the change in their T1 hypointensities, the change in the volume of their T2 lesions, or their annualized relapse rate or mean time to relapse.

When daclizumab treatment was discontinued in a 48-week posttreatment period, the formation of lesions returned to about the same level in all groups.

In a post hoc analysis, higher counts of CD56

Daclizumab-treated patients who were in the highest quartile of CD56

“Identifying the physiological mechanism or mechanisms that lead to the expansion of [CD56

Serious adverse events in patients treated with daclizumab most often consisted of infections and infestations, none of which were opportunistic or resulted in death. Two patients who received daclizumab developed malignant disease, one with breast cancer and one with a recurrence of pseudomyxoma peritonei.

My Take

Drug Is Good Candidate for Phase III

In this phase II trial, treatment with high-dose daclizumab significantly reduced the number of gadolinium-enhancing lesions in MS patients, which suggests that it is a good candidate to move forward into phase III clinical trials. However, because the treatment phase of the trial lasted only 6 months, we cannot know yet what effect the drug has on the rate of relapse and other clinical measures.

It seems to be a reasonable approach to further study the use of daclizumab as an add-on therapy to interferon beta, but it will be important to know the full safety profile of daclizumab when used with other MS therapies. Progressive multifocal leukoencephalopathy has been associated with other monoclonal antibodies such as natalizumab (Tysabri) and rituximab (Rituxan), especially when used in combination with other immunomodulating or immunosuppressive agents.

Daclizumab did not seem to have a worrisome side effect profile, but some patients developed a skin rash, particularly those in the group that was given low-dose daclizumab.

Major Finding: Patients taking 2 mg/kg of daclizumab every 2 weeks plus interferon beta had significantly fewer new or enlarged gadolinium-enhancing lesions after 24 weeks of treatment than did those taking interferon beta plus placebo (1.32 vs. 4.75).

Data Source: CHOICE study: Double-blind, randomized, placebo-controlled, phase II trial of 230 patients with active relapsing MS

Disclosures: Many investigators reported potential conflicts of interest with Biogen Idec Inc., maker of the MS medications, Tysabri and Avonex. Some of the investigators are employed by and own stock with either Biogen Idec or Facet Biotech Corp., both of which funded the trial. Dr. Greenberg and Dr. Stüve disclosed potential conflicts of interest with several manufacturers of MS drugs.

Multiple sclerosis patients who experience relapsing disease while taking interferon beta might be able to reduce their number of new or enlarging lesions by adding the humanized monoclonal antibody daclizumab.

Besides reducing the risk of lesion growth and formation, the antibody might exert at least part of its effects through a mechanism that is now suggested by several lines of evidence to be a potential drug target and an important part of further understanding the pathogenesis of the disease, Dr. Daniel Wynn of Consultants in Neurology Multiple Sclerosis Center, Northbrook, Ill., and his associates reported (Lancet Neurol. 2010 Feb. 16 [doi:10.1016/S1474-4422(10)70033-8

Daclizumab (Zenapax) has been already approved by the Food and Drug Administration for the prophylaxis of acute organ rejection in patients receiving renal transplants.

“The true effects of this trial and previous observations on daclizumab might be more far-reaching than they seem at first glance,” Dr. Olaf Stüve and Dr. Benjamin M. Greenberg wrote in an editorial (Lancet Neurol. 2010 Feb. 16 [doi:10.1016/S1474-4422(10)70032-6

Daclizumab was thought to inhibit T-cell proliferation and activation by binding to the CD25 subunit of the human high-affinity interleukin-2 receptor, but in this and other studies of MS patients treated with daclizumab, T cells have shown normal proliferative and activation responses.

Rather than reduce the activation or proliferation of T cells, Dr. Wynn and his colleagues found that the reduction of disease activity with daclizumab appears to be associated with an expansion of a regulatory subset of CD56

In the 51-center CHOICE study, the investigators randomized 75 patients to daclizumab 2 mg/kg every 2 weeks, 78 patients to daclizumab 1 mg/kg every 4 weeks, and 77 patients to placebo. These patients had a mean age of about 40 years and continued to take their baseline interferon beta regimens. Patients in each treatment arm averaged about 2.5 relapses in the previous 2 years and had a mean Expanded Disability Status Scale score of 3 (0 = normal; 10 = death). All of the patients had experienced at least one relapse or at least one gadolinium-enhancing brain or spinal cord lesion in the previous year while on a stable interferon beta regimen.

No significant differences were noted between the low-dose daclizumab and placebo groups on any of the imaging or clinical end points.

However, at 24 weeks, significantly fewer new or enlarged gadolinium-enhancing lesions had developed in the high-dose daclizumab group, compared with the placebo-treated group (mean of 1.32 lesions vs. 4.75, respectively). Enlarged lesions were defined by at least a 50% increase in size for lesions measuring at least 5 mm in diameter and by at least a 20% increase in size for lesions less than 5 mm.

High-dose daclizumab also was associated with a significantly lower number of new gadolinium-enhancing lesions alone, compared with placebo (mean of 1.18 vs. 3.95).

By 24 weeks, the high-dose daclizumab patients developed significantly fewer T2 lesions than did placebo-treated patients (1.1 vs. 3.4).

None of the groups were significantly different in terms of the change in their T1 hypointensities, the change in the volume of their T2 lesions, or their annualized relapse rate or mean time to relapse.

When daclizumab treatment was discontinued in a 48-week posttreatment period, the formation of lesions returned to about the same level in all groups.

In a post hoc analysis, higher counts of CD56

Daclizumab-treated patients who were in the highest quartile of CD56

“Identifying the physiological mechanism or mechanisms that lead to the expansion of [CD56

Serious adverse events in patients treated with daclizumab most often consisted of infections and infestations, none of which were opportunistic or resulted in death. Two patients who received daclizumab developed malignant disease, one with breast cancer and one with a recurrence of pseudomyxoma peritonei.

My Take

Drug Is Good Candidate for Phase III

In this phase II trial, treatment with high-dose daclizumab significantly reduced the number of gadolinium-enhancing lesions in MS patients, which suggests that it is a good candidate to move forward into phase III clinical trials. However, because the treatment phase of the trial lasted only 6 months, we cannot know yet what effect the drug has on the rate of relapse and other clinical measures.

It seems to be a reasonable approach to further study the use of daclizumab as an add-on therapy to interferon beta, but it will be important to know the full safety profile of daclizumab when used with other MS therapies. Progressive multifocal leukoencephalopathy has been associated with other monoclonal antibodies such as natalizumab (Tysabri) and rituximab (Rituxan), especially when used in combination with other immunomodulating or immunosuppressive agents.

Daclizumab did not seem to have a worrisome side effect profile, but some patients developed a skin rash, particularly those in the group that was given low-dose daclizumab.

Major Finding: Patients taking 2 mg/kg of daclizumab every 2 weeks plus interferon beta had significantly fewer new or enlarged gadolinium-enhancing lesions after 24 weeks of treatment than did those taking interferon beta plus placebo (1.32 vs. 4.75).

Data Source: CHOICE study: Double-blind, randomized, placebo-controlled, phase II trial of 230 patients with active relapsing MS

Disclosures: Many investigators reported potential conflicts of interest with Biogen Idec Inc., maker of the MS medications, Tysabri and Avonex. Some of the investigators are employed by and own stock with either Biogen Idec or Facet Biotech Corp., both of which funded the trial. Dr. Greenberg and Dr. Stüve disclosed potential conflicts of interest with several manufacturers of MS drugs.

Multiple sclerosis patients who experience relapsing disease while taking interferon beta might be able to reduce their number of new or enlarging lesions by adding the humanized monoclonal antibody daclizumab.

Besides reducing the risk of lesion growth and formation, the antibody might exert at least part of its effects through a mechanism that is now suggested by several lines of evidence to be a potential drug target and an important part of further understanding the pathogenesis of the disease, Dr. Daniel Wynn of Consultants in Neurology Multiple Sclerosis Center, Northbrook, Ill., and his associates reported (Lancet Neurol. 2010 Feb. 16 [doi:10.1016/S1474-4422(10)70033-8

Daclizumab (Zenapax) has been already approved by the Food and Drug Administration for the prophylaxis of acute organ rejection in patients receiving renal transplants.

“The true effects of this trial and previous observations on daclizumab might be more far-reaching than they seem at first glance,” Dr. Olaf Stüve and Dr. Benjamin M. Greenberg wrote in an editorial (Lancet Neurol. 2010 Feb. 16 [doi:10.1016/S1474-4422(10)70032-6

Daclizumab was thought to inhibit T-cell proliferation and activation by binding to the CD25 subunit of the human high-affinity interleukin-2 receptor, but in this and other studies of MS patients treated with daclizumab, T cells have shown normal proliferative and activation responses.

Rather than reduce the activation or proliferation of T cells, Dr. Wynn and his colleagues found that the reduction of disease activity with daclizumab appears to be associated with an expansion of a regulatory subset of CD56

In the 51-center CHOICE study, the investigators randomized 75 patients to daclizumab 2 mg/kg every 2 weeks, 78 patients to daclizumab 1 mg/kg every 4 weeks, and 77 patients to placebo. These patients had a mean age of about 40 years and continued to take their baseline interferon beta regimens. Patients in each treatment arm averaged about 2.5 relapses in the previous 2 years and had a mean Expanded Disability Status Scale score of 3 (0 = normal; 10 = death). All of the patients had experienced at least one relapse or at least one gadolinium-enhancing brain or spinal cord lesion in the previous year while on a stable interferon beta regimen.

No significant differences were noted between the low-dose daclizumab and placebo groups on any of the imaging or clinical end points.

However, at 24 weeks, significantly fewer new or enlarged gadolinium-enhancing lesions had developed in the high-dose daclizumab group, compared with the placebo-treated group (mean of 1.32 lesions vs. 4.75, respectively). Enlarged lesions were defined by at least a 50% increase in size for lesions measuring at least 5 mm in diameter and by at least a 20% increase in size for lesions less than 5 mm.

High-dose daclizumab also was associated with a significantly lower number of new gadolinium-enhancing lesions alone, compared with placebo (mean of 1.18 vs. 3.95).

By 24 weeks, the high-dose daclizumab patients developed significantly fewer T2 lesions than did placebo-treated patients (1.1 vs. 3.4).

None of the groups were significantly different in terms of the change in their T1 hypointensities, the change in the volume of their T2 lesions, or their annualized relapse rate or mean time to relapse.

When daclizumab treatment was discontinued in a 48-week posttreatment period, the formation of lesions returned to about the same level in all groups.

In a post hoc analysis, higher counts of CD56

Daclizumab-treated patients who were in the highest quartile of CD56

“Identifying the physiological mechanism or mechanisms that lead to the expansion of [CD56

Serious adverse events in patients treated with daclizumab most often consisted of infections and infestations, none of which were opportunistic or resulted in death. Two patients who received daclizumab developed malignant disease, one with breast cancer and one with a recurrence of pseudomyxoma peritonei.

My Take

Drug Is Good Candidate for Phase III

In this phase II trial, treatment with high-dose daclizumab significantly reduced the number of gadolinium-enhancing lesions in MS patients, which suggests that it is a good candidate to move forward into phase III clinical trials. However, because the treatment phase of the trial lasted only 6 months, we cannot know yet what effect the drug has on the rate of relapse and other clinical measures.

It seems to be a reasonable approach to further study the use of daclizumab as an add-on therapy to interferon beta, but it will be important to know the full safety profile of daclizumab when used with other MS therapies. Progressive multifocal leukoencephalopathy has been associated with other monoclonal antibodies such as natalizumab (Tysabri) and rituximab (Rituxan), especially when used in combination with other immunomodulating or immunosuppressive agents.

Daclizumab did not seem to have a worrisome side effect profile, but some patients developed a skin rash, particularly those in the group that was given low-dose daclizumab.

BOSTON—Patients with tuberous sclerosis complex (TSC) may benefit from novel therapies targeting idoleamine 2,3-dioxygenase (IDO) and major vault protein (MVP), researchers at Wayne State University in Detroit reported at the American Epilepsy Society meeting. Carlos Batista, a graduate student in the Translational Neuroscience Program, and colleagues studied cortical tubers that were surgically removed from 12 children with TSC and found elevated tryptophan metabolism and expressions of IDO and MVP.

“Cortical tubers express large numbers of activated microglia, macrophages, and T lymphocytes, thus suggesting activation of inflammatory pathways,” the researchers noted. “Under conditions that cause activation of inflammatory pathways, IDO (the rate-limiting enzyme of tryptophan metabolism by the kynurenine pathway in the brain) is induced by IFN-γ.”

Furthermore, MVP, which is associated with multidrug resistance, is also induced by IFN-γ. Researchers hypothesized and found that the effect of inflammation on MVP and IDO in epileptogenic tumors may be different in TSC1 and TSC2 mutations. Patients with TSC2 had a higher expression of MVP than those with TSC1, which may explain the more severe course of the disease in TSC2 patients.

BOSTON—Patients with tuberous sclerosis complex (TSC) may benefit from novel therapies targeting idoleamine 2,3-dioxygenase (IDO) and major vault protein (MVP), researchers at Wayne State University in Detroit reported at the American Epilepsy Society meeting. Carlos Batista, a graduate student in the Translational Neuroscience Program, and colleagues studied cortical tubers that were surgically removed from 12 children with TSC and found elevated tryptophan metabolism and expressions of IDO and MVP.

“Cortical tubers express large numbers of activated microglia, macrophages, and T lymphocytes, thus suggesting activation of inflammatory pathways,” the researchers noted. “Under conditions that cause activation of inflammatory pathways, IDO (the rate-limiting enzyme of tryptophan metabolism by the kynurenine pathway in the brain) is induced by IFN-γ.”

Furthermore, MVP, which is associated with multidrug resistance, is also induced by IFN-γ. Researchers hypothesized and found that the effect of inflammation on MVP and IDO in epileptogenic tumors may be different in TSC1 and TSC2 mutations. Patients with TSC2 had a higher expression of MVP than those with TSC1, which may explain the more severe course of the disease in TSC2 patients.

BOSTON—Patients with tuberous sclerosis complex (TSC) may benefit from novel therapies targeting idoleamine 2,3-dioxygenase (IDO) and major vault protein (MVP), researchers at Wayne State University in Detroit reported at the American Epilepsy Society meeting. Carlos Batista, a graduate student in the Translational Neuroscience Program, and colleagues studied cortical tubers that were surgically removed from 12 children with TSC and found elevated tryptophan metabolism and expressions of IDO and MVP.

“Cortical tubers express large numbers of activated microglia, macrophages, and T lymphocytes, thus suggesting activation of inflammatory pathways,” the researchers noted. “Under conditions that cause activation of inflammatory pathways, IDO (the rate-limiting enzyme of tryptophan metabolism by the kynurenine pathway in the brain) is induced by IFN-γ.”

Furthermore, MVP, which is associated with multidrug resistance, is also induced by IFN-γ. Researchers hypothesized and found that the effect of inflammation on MVP and IDO in epileptogenic tumors may be different in TSC1 and TSC2 mutations. Patients with TSC2 had a higher expression of MVP than those with TSC1, which may explain the more severe course of the disease in TSC2 patients.

BALTIMORE — Surveillance programs for progressive multifocal leukoencephalopathy have many hurdles to clear before any become a reality in federal agencies or state health departments, despite concern over new cases that are associated with the use of monoclonal antibody therapies.

Dr. James J. Sejvar of the Centers for Disease Control and Prevention said that in addition to a lack of funding, attempts to conduct surveillance for progressive multifocal leukoencephalopathy (PML) are hampered by a lack of clear diagnostic criteria, a definition for a confirmed case, and case validation methods.

Dr. Sejvar, a neurologist and epidemiologist with the division of viral and rickettsial diseases at the CDC's National Center for Zoonotic, Vector-Borne, and Enteric Disease, described potential benefits and limitations of various approaches to PML surveillance at the annual meeting of the American Neurological Association.

Reports thus far have estimated that PML occurs in 1 of every 1,000 patients exposed to natalizumab (Tysabri), 1 of every 500 exposed to efalizumab (which has been taken off the U.S. market), and at an unknown, but probably lower, rate in patients exposed to rituximab (Rituxan).

National surveillance for PML could be conducted by making it a nationally notifiable infectious disease, establishing a national registry, or by gathering information from physicians, states, or laboratories.

A mechanism for surveillance still would need to have the capacity to determine a case definition of PML, which samples of patient data should be analyzed, the level of diagnostic certainty necessary for prompt reporting/confirming of cases, who should analyze patients' samples and data, and how it would be funded, Dr. Sejvar said.

NNIDs Designation

The CDC could add PML to the list of nationally notifiable infectious diseases (NNIDs), which are normally restricted to diseases with significant risk to public health. Although a rough infrastructure is already in place to add PML, and the condition would gain greater attention from physicians if it were added to the list, Dr. Sejvar said that “making it reportable doesn't mean it will be reported.”

Diagnosing PML is difficult in part because of inaccurate reporting of cases, which points to the need for methods for validating cases. PML is probably also underascertained in clinics, he said, noting that no simple laboratory test for it is available.

Dr. Sejvar said state governments are unlikely to view PML as a public health imperative that is worthy of the investments that would have to be made to conduct surveillance.

National Registry for PML

Another option would be for PML to be tracked in a national registry by the Agency for Toxic Substances and Diseases Registry (ATSDR). The congressionally mandated national amyotrophic lateral sclerosis registry that was recently developed with the ATSDR could serve as a template, Dr. Sejvar said.

“This would provide for an infrastructure to start to get a handle on PML and also allow for the collection of detailed clinical information.”

The registry would rely on self-reports by patients and entries from physicians, and would need funding and endorsement from various stakeholders, he said. Congress would have to be actively lobbied for a national PML registry.

Active, Physician-Based Surveillance

Surveillance for PML under the CDC's Emerging Infections Program, a network formed by the CDC and 10 state health departments covering 44 million people, would provide a relatively accurate estimation of incidence and prevalence. The EIP contains sites with many tertiary neurologic care institutes where patients with PML would be best diagnosed, Dr. Sejvar noted.

The proactive outreach approach of the EIP would provide direct contact with the neurologic community, but it is limited by the resources of its partners. Adding PML surveillance would require endorsement by principal investigators at all EIP sites, who are unlikely to view PML as important enough to add.

State-Based Surveillance

State-based surveillance by the CDC or ATSDR, performed in cooperation with the Council of State and Territorial Epidemiologists (CSTE), “may be one of the best options,” Dr. Sejvar said.

The CSTE is already involved in surveillance for Creutzfeldt-Jakob disease, another rare neurologic disorder that is difficult to diagnose. If PML surveillance was performed with CSTE, state surveillance officers would identify and report cases to the CDC. The CSTE would need to receive a proposal to add PML to its surveillance list and then endorse it.

There is also potential for collaborating with the National Prion Disease Pathology Surveillance Center to confirm cases pathologically, Dr. Sejvar said.

Laboratory-Based Surveillance

A system of laboratory-based surveillance is already used for other infectious diseases, particularly ones that can be readily identified in the lab and then reported to state health departments and the CDC. If a lab-based system was assembled, investigators could collect data rapidly from the relatively few labs that perform JC virus polymerase chain reaction assays, requiring minimal resources, Dr. Sejvar said.

However, lab-based surveillance would produce many false-negative results. Clinical data, which would be hard to obtain, would be necessary to interpret the lab data.

BALTIMORE — Surveillance programs for progressive multifocal leukoencephalopathy have many hurdles to clear before any become a reality in federal agencies or state health departments, despite concern over new cases that are associated with the use of monoclonal antibody therapies.

Dr. James J. Sejvar of the Centers for Disease Control and Prevention said that in addition to a lack of funding, attempts to conduct surveillance for progressive multifocal leukoencephalopathy (PML) are hampered by a lack of clear diagnostic criteria, a definition for a confirmed case, and case validation methods.

Dr. Sejvar, a neurologist and epidemiologist with the division of viral and rickettsial diseases at the CDC's National Center for Zoonotic, Vector-Borne, and Enteric Disease, described potential benefits and limitations of various approaches to PML surveillance at the annual meeting of the American Neurological Association.

Reports thus far have estimated that PML occurs in 1 of every 1,000 patients exposed to natalizumab (Tysabri), 1 of every 500 exposed to efalizumab (which has been taken off the U.S. market), and at an unknown, but probably lower, rate in patients exposed to rituximab (Rituxan).

National surveillance for PML could be conducted by making it a nationally notifiable infectious disease, establishing a national registry, or by gathering information from physicians, states, or laboratories.

A mechanism for surveillance still would need to have the capacity to determine a case definition of PML, which samples of patient data should be analyzed, the level of diagnostic certainty necessary for prompt reporting/confirming of cases, who should analyze patients' samples and data, and how it would be funded, Dr. Sejvar said.

NNIDs Designation

The CDC could add PML to the list of nationally notifiable infectious diseases (NNIDs), which are normally restricted to diseases with significant risk to public health. Although a rough infrastructure is already in place to add PML, and the condition would gain greater attention from physicians if it were added to the list, Dr. Sejvar said that “making it reportable doesn't mean it will be reported.”

Diagnosing PML is difficult in part because of inaccurate reporting of cases, which points to the need for methods for validating cases. PML is probably also underascertained in clinics, he said, noting that no simple laboratory test for it is available.

Dr. Sejvar said state governments are unlikely to view PML as a public health imperative that is worthy of the investments that would have to be made to conduct surveillance.

National Registry for PML

Another option would be for PML to be tracked in a national registry by the Agency for Toxic Substances and Diseases Registry (ATSDR). The congressionally mandated national amyotrophic lateral sclerosis registry that was recently developed with the ATSDR could serve as a template, Dr. Sejvar said.

“This would provide for an infrastructure to start to get a handle on PML and also allow for the collection of detailed clinical information.”

The registry would rely on self-reports by patients and entries from physicians, and would need funding and endorsement from various stakeholders, he said. Congress would have to be actively lobbied for a national PML registry.

Active, Physician-Based Surveillance

Surveillance for PML under the CDC's Emerging Infections Program, a network formed by the CDC and 10 state health departments covering 44 million people, would provide a relatively accurate estimation of incidence and prevalence. The EIP contains sites with many tertiary neurologic care institutes where patients with PML would be best diagnosed, Dr. Sejvar noted.

The proactive outreach approach of the EIP would provide direct contact with the neurologic community, but it is limited by the resources of its partners. Adding PML surveillance would require endorsement by principal investigators at all EIP sites, who are unlikely to view PML as important enough to add.

State-Based Surveillance

State-based surveillance by the CDC or ATSDR, performed in cooperation with the Council of State and Territorial Epidemiologists (CSTE), “may be one of the best options,” Dr. Sejvar said.

The CSTE is already involved in surveillance for Creutzfeldt-Jakob disease, another rare neurologic disorder that is difficult to diagnose. If PML surveillance was performed with CSTE, state surveillance officers would identify and report cases to the CDC. The CSTE would need to receive a proposal to add PML to its surveillance list and then endorse it.

There is also potential for collaborating with the National Prion Disease Pathology Surveillance Center to confirm cases pathologically, Dr. Sejvar said.

Laboratory-Based Surveillance

A system of laboratory-based surveillance is already used for other infectious diseases, particularly ones that can be readily identified in the lab and then reported to state health departments and the CDC. If a lab-based system was assembled, investigators could collect data rapidly from the relatively few labs that perform JC virus polymerase chain reaction assays, requiring minimal resources, Dr. Sejvar said.

However, lab-based surveillance would produce many false-negative results. Clinical data, which would be hard to obtain, would be necessary to interpret the lab data.

BALTIMORE — Surveillance programs for progressive multifocal leukoencephalopathy have many hurdles to clear before any become a reality in federal agencies or state health departments, despite concern over new cases that are associated with the use of monoclonal antibody therapies.

Dr. James J. Sejvar of the Centers for Disease Control and Prevention said that in addition to a lack of funding, attempts to conduct surveillance for progressive multifocal leukoencephalopathy (PML) are hampered by a lack of clear diagnostic criteria, a definition for a confirmed case, and case validation methods.

Dr. Sejvar, a neurologist and epidemiologist with the division of viral and rickettsial diseases at the CDC's National Center for Zoonotic, Vector-Borne, and Enteric Disease, described potential benefits and limitations of various approaches to PML surveillance at the annual meeting of the American Neurological Association.

Reports thus far have estimated that PML occurs in 1 of every 1,000 patients exposed to natalizumab (Tysabri), 1 of every 500 exposed to efalizumab (which has been taken off the U.S. market), and at an unknown, but probably lower, rate in patients exposed to rituximab (Rituxan).

National surveillance for PML could be conducted by making it a nationally notifiable infectious disease, establishing a national registry, or by gathering information from physicians, states, or laboratories.

A mechanism for surveillance still would need to have the capacity to determine a case definition of PML, which samples of patient data should be analyzed, the level of diagnostic certainty necessary for prompt reporting/confirming of cases, who should analyze patients' samples and data, and how it would be funded, Dr. Sejvar said.

NNIDs Designation

The CDC could add PML to the list of nationally notifiable infectious diseases (NNIDs), which are normally restricted to diseases with significant risk to public health. Although a rough infrastructure is already in place to add PML, and the condition would gain greater attention from physicians if it were added to the list, Dr. Sejvar said that “making it reportable doesn't mean it will be reported.”

Diagnosing PML is difficult in part because of inaccurate reporting of cases, which points to the need for methods for validating cases. PML is probably also underascertained in clinics, he said, noting that no simple laboratory test for it is available.

Dr. Sejvar said state governments are unlikely to view PML as a public health imperative that is worthy of the investments that would have to be made to conduct surveillance.

National Registry for PML

Another option would be for PML to be tracked in a national registry by the Agency for Toxic Substances and Diseases Registry (ATSDR). The congressionally mandated national amyotrophic lateral sclerosis registry that was recently developed with the ATSDR could serve as a template, Dr. Sejvar said.

“This would provide for an infrastructure to start to get a handle on PML and also allow for the collection of detailed clinical information.”

The registry would rely on self-reports by patients and entries from physicians, and would need funding and endorsement from various stakeholders, he said. Congress would have to be actively lobbied for a national PML registry.

Active, Physician-Based Surveillance

Surveillance for PML under the CDC's Emerging Infections Program, a network formed by the CDC and 10 state health departments covering 44 million people, would provide a relatively accurate estimation of incidence and prevalence. The EIP contains sites with many tertiary neurologic care institutes where patients with PML would be best diagnosed, Dr. Sejvar noted.

The proactive outreach approach of the EIP would provide direct contact with the neurologic community, but it is limited by the resources of its partners. Adding PML surveillance would require endorsement by principal investigators at all EIP sites, who are unlikely to view PML as important enough to add.

State-Based Surveillance

State-based surveillance by the CDC or ATSDR, performed in cooperation with the Council of State and Territorial Epidemiologists (CSTE), “may be one of the best options,” Dr. Sejvar said.

The CSTE is already involved in surveillance for Creutzfeldt-Jakob disease, another rare neurologic disorder that is difficult to diagnose. If PML surveillance was performed with CSTE, state surveillance officers would identify and report cases to the CDC. The CSTE would need to receive a proposal to add PML to its surveillance list and then endorse it.

There is also potential for collaborating with the National Prion Disease Pathology Surveillance Center to confirm cases pathologically, Dr. Sejvar said.

Laboratory-Based Surveillance

A system of laboratory-based surveillance is already used for other infectious diseases, particularly ones that can be readily identified in the lab and then reported to state health departments and the CDC. If a lab-based system was assembled, investigators could collect data rapidly from the relatively few labs that perform JC virus polymerase chain reaction assays, requiring minimal resources, Dr. Sejvar said.

However, lab-based surveillance would produce many false-negative results. Clinical data, which would be hard to obtain, would be necessary to interpret the lab data.

Major Finding: “Real-world” multiple sclerosis patients treated with natalizumab had rates of adverse events and reduction in relapses similar to those observed in patients in phase III trials.

Data Source: Ongoing postmarketing observational study of 1,011 patients.

Disclosures: Study funded by Biogen Idec Inc.; Dr. Trojano, consulting or speaking fees from Biogen Idec and research funding from Merck Serono.

BANGKOK, THAILAND — The effects and adverse event profile of natalizumab in multiple sclerosis patients seen in highly controlled phase III trials continue to be observed in patients who are participating in an ongoing, postmarketing observational trial of the drug.

The Tysabri Observational Program (TOP) is an ongoing evaluation of the drug's effect in 1,011 patients, whose baseline characteristics were quite different from those of patients included in the AFFIRM (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis) trials, on which the drug's approval was based, said Dr. Maria Trojano, who presented the results at the World Congress of Neurology.

The AFFIRM trial lasted 2 years, and showed a 68% reduction in the relapse rate among all patients, as well as a 42% reduction in sustained EDSS progression. Natalizumab (Tysabri) was also effective in patients with highly active disease, reducing the annual relapse rate by 81%, and the EDSS progression rate by 53%. Safety was good, with a 4% rate of adverse events, 1% of which were considered serious.

The TOP study (www.clinicaltrials.gov/ct2/show/NCT00493298

The question TOP must answer, Dr. Trojano said, is: “Does natalizumab in real life produce a similar highly reducing effect on disease activity and progression, while keeping the same safety?”

At baseline, TOP's cohort was significantly older than those in AFFIRM (38 vs. 36 years), with a longer mean duration of disease (7.5 vs. 5 years), and a worse mean score on the Expanded Disability Status Scale (EDSS; 3.7 vs. 2.3). TOP patients also had a higher annual relapse rate than did AFFIRM patients (2.03 vs. 1.53), noted Dr. Trojano of the University of Bari, Italy.

As of July 2009, patients in TOP had taken a mean of 7 doses of natalizumab, giving a base of 556 person-years to evaluate.

Natalizumab was associated with a steep decline in annualized relapse rate, dropping from a mean of 2 to less than 0.5 in the first month of therapy. Throughout the next 12 months, the mean relapse rate stayed below 0.5. This pattern mirrors that seen in the AFFIRM trial, which found relapse rates below 0.5 throughout its 24-month follow-up period.

The 292 TOP patients who have completed a full 12 months of follow-up have remained clinically stable, with an EDSS score of 3.6, compared with 3.8 at baseline.

As of July 14, there had been 46 serious adverse events reported in TOP patients (4.3%). Those included 10 infections (including 4 cases of herpes zoster and 2 pneumonias); 9 hypersensitivity reactions; 19 “miscellaneous” events; and 8 events that were not yet coded.

However, Dr. Trojano said, since TOP lacked a randomized control group, an independent 5-year study will create an external patient cohort to be used for a comparison to TOP patients.

The Multiple Sclerosis Comparator Study of Efficacy of Treatment (MSCOMET) trial will provide more reliable information about the effectiveness of natalizumab.

MSCOMET will prospectively assesses clinical effectiveness of interferon-beta or glatiramer acetate in a cohort of patients with relapsing-remitting MS.

Patients will be recruited from some centers participating in the International MSBase Registry in Melbourne, Australia. The external cohort will be selected in the MSBase Registry by a propensity score-matching technique.

Major Finding: “Real-world” multiple sclerosis patients treated with natalizumab had rates of adverse events and reduction in relapses similar to those observed in patients in phase III trials.

Data Source: Ongoing postmarketing observational study of 1,011 patients.

Disclosures: Study funded by Biogen Idec Inc.; Dr. Trojano, consulting or speaking fees from Biogen Idec and research funding from Merck Serono.

BANGKOK, THAILAND — The effects and adverse event profile of natalizumab in multiple sclerosis patients seen in highly controlled phase III trials continue to be observed in patients who are participating in an ongoing, postmarketing observational trial of the drug.

The Tysabri Observational Program (TOP) is an ongoing evaluation of the drug's effect in 1,011 patients, whose baseline characteristics were quite different from those of patients included in the AFFIRM (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis) trials, on which the drug's approval was based, said Dr. Maria Trojano, who presented the results at the World Congress of Neurology.

The AFFIRM trial lasted 2 years, and showed a 68% reduction in the relapse rate among all patients, as well as a 42% reduction in sustained EDSS progression. Natalizumab (Tysabri) was also effective in patients with highly active disease, reducing the annual relapse rate by 81%, and the EDSS progression rate by 53%. Safety was good, with a 4% rate of adverse events, 1% of which were considered serious.

The TOP study (www.clinicaltrials.gov/ct2/show/NCT00493298

The question TOP must answer, Dr. Trojano said, is: “Does natalizumab in real life produce a similar highly reducing effect on disease activity and progression, while keeping the same safety?”

At baseline, TOP's cohort was significantly older than those in AFFIRM (38 vs. 36 years), with a longer mean duration of disease (7.5 vs. 5 years), and a worse mean score on the Expanded Disability Status Scale (EDSS; 3.7 vs. 2.3). TOP patients also had a higher annual relapse rate than did AFFIRM patients (2.03 vs. 1.53), noted Dr. Trojano of the University of Bari, Italy.

As of July 2009, patients in TOP had taken a mean of 7 doses of natalizumab, giving a base of 556 person-years to evaluate.

Natalizumab was associated with a steep decline in annualized relapse rate, dropping from a mean of 2 to less than 0.5 in the first month of therapy. Throughout the next 12 months, the mean relapse rate stayed below 0.5. This pattern mirrors that seen in the AFFIRM trial, which found relapse rates below 0.5 throughout its 24-month follow-up period.

The 292 TOP patients who have completed a full 12 months of follow-up have remained clinically stable, with an EDSS score of 3.6, compared with 3.8 at baseline.

As of July 14, there had been 46 serious adverse events reported in TOP patients (4.3%). Those included 10 infections (including 4 cases of herpes zoster and 2 pneumonias); 9 hypersensitivity reactions; 19 “miscellaneous” events; and 8 events that were not yet coded.

However, Dr. Trojano said, since TOP lacked a randomized control group, an independent 5-year study will create an external patient cohort to be used for a comparison to TOP patients.

The Multiple Sclerosis Comparator Study of Efficacy of Treatment (MSCOMET) trial will provide more reliable information about the effectiveness of natalizumab.

MSCOMET will prospectively assesses clinical effectiveness of interferon-beta or glatiramer acetate in a cohort of patients with relapsing-remitting MS.

Patients will be recruited from some centers participating in the International MSBase Registry in Melbourne, Australia. The external cohort will be selected in the MSBase Registry by a propensity score-matching technique.

Major Finding: “Real-world” multiple sclerosis patients treated with natalizumab had rates of adverse events and reduction in relapses similar to those observed in patients in phase III trials.

Data Source: Ongoing postmarketing observational study of 1,011 patients.

Disclosures: Study funded by Biogen Idec Inc.; Dr. Trojano, consulting or speaking fees from Biogen Idec and research funding from Merck Serono.

BANGKOK, THAILAND — The effects and adverse event profile of natalizumab in multiple sclerosis patients seen in highly controlled phase III trials continue to be observed in patients who are participating in an ongoing, postmarketing observational trial of the drug.

The Tysabri Observational Program (TOP) is an ongoing evaluation of the drug's effect in 1,011 patients, whose baseline characteristics were quite different from those of patients included in the AFFIRM (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis) trials, on which the drug's approval was based, said Dr. Maria Trojano, who presented the results at the World Congress of Neurology.

The AFFIRM trial lasted 2 years, and showed a 68% reduction in the relapse rate among all patients, as well as a 42% reduction in sustained EDSS progression. Natalizumab (Tysabri) was also effective in patients with highly active disease, reducing the annual relapse rate by 81%, and the EDSS progression rate by 53%. Safety was good, with a 4% rate of adverse events, 1% of which were considered serious.

The TOP study (www.clinicaltrials.gov/ct2/show/NCT00493298

The question TOP must answer, Dr. Trojano said, is: “Does natalizumab in real life produce a similar highly reducing effect on disease activity and progression, while keeping the same safety?”

At baseline, TOP's cohort was significantly older than those in AFFIRM (38 vs. 36 years), with a longer mean duration of disease (7.5 vs. 5 years), and a worse mean score on the Expanded Disability Status Scale (EDSS; 3.7 vs. 2.3). TOP patients also had a higher annual relapse rate than did AFFIRM patients (2.03 vs. 1.53), noted Dr. Trojano of the University of Bari, Italy.

As of July 2009, patients in TOP had taken a mean of 7 doses of natalizumab, giving a base of 556 person-years to evaluate.

Natalizumab was associated with a steep decline in annualized relapse rate, dropping from a mean of 2 to less than 0.5 in the first month of therapy. Throughout the next 12 months, the mean relapse rate stayed below 0.5. This pattern mirrors that seen in the AFFIRM trial, which found relapse rates below 0.5 throughout its 24-month follow-up period.

The 292 TOP patients who have completed a full 12 months of follow-up have remained clinically stable, with an EDSS score of 3.6, compared with 3.8 at baseline.

As of July 14, there had been 46 serious adverse events reported in TOP patients (4.3%). Those included 10 infections (including 4 cases of herpes zoster and 2 pneumonias); 9 hypersensitivity reactions; 19 “miscellaneous” events; and 8 events that were not yet coded.

However, Dr. Trojano said, since TOP lacked a randomized control group, an independent 5-year study will create an external patient cohort to be used for a comparison to TOP patients.

The Multiple Sclerosis Comparator Study of Efficacy of Treatment (MSCOMET) trial will provide more reliable information about the effectiveness of natalizumab.

MSCOMET will prospectively assesses clinical effectiveness of interferon-beta or glatiramer acetate in a cohort of patients with relapsing-remitting MS.

Patients will be recruited from some centers participating in the International MSBase Registry in Melbourne, Australia. The external cohort will be selected in the MSBase Registry by a propensity score-matching technique.

Major Finding: Abrupt discontinuation of natalizumab coincided with a surge in gadolinium-enhancing lesions on MRI that mostly resolved by 9 months without any clinical deterioration.

Data Source: Case series of 11 patients who had received natalizumab infusions before abruptly discontinuing the therapy

Disclosures: Dr. Khan said the study was independently funded and he did not have any financial declarations to make.

BANGKOK, THAILAND — Patients with multiple sclerosis who abruptly discontinue natalizumab treatment may develop a sudden surge in the number of gadolinium-enhancing lesions apparent on imaging, which seems to resolve by 9 months.

The phenomenon is probably a reaction to the sudden resurgence of lymphocytes into the brain—a central nervous system form of immune reconstitution inflammatory syndrome, Dr. Omar Khan said at the World Congress of Neurology.

Although the dramatic imaging changes aren't accompanied by clinical deterioration, about 22% of the lesions did develop into nonenhancing T1 hypointensities, said Dr. Khan, director of the Wayne State University Multiple Sclerosis Clinical Research Center and Radiology Image Analysis Laboratory, Detroit. “Some patients may accumulate a lot of irreversible neuronal damage in this short period of time. And although it's too soon to know for sure, my gut feeling is that over 3 or 4 years, there might be some consequences.”

Dr. Khan presented a case series of 11 patients with MS who had received natalizumab infusions before stopping the treatment abruptly. The reasons for discontinuation included infusion site reactions, the development of neutralizing antibodies, changes in insurance coverage, and worries about developing progressive multifocal leukoencephalopathy.

The patients' mean age was 36 years. They had undergone a mean of 13 natalizumab infusions, although that number ranged from 8 to 21. Before taking natalizumab, their mean relapse rate was 1.6/year; the mean relapse rate at discontinuation of the drug was 0.1/year. All patients were negative for John Cunningham (JC) virus.

Before beginning natalizumab, the patients had a mean of 12 T2 lesions, two T1 lesions and 20 gadolinium-enhancing lesions on MRI. Three months after stopping the drug, the numbers of lesions increased significantly, to 17 T2 lesions, 13 T1 lesions, and 137 gadolinium-enhancing lesions. Overall, 93 of the lesions appeared in brain areas that were previously normal-appearing on imaging.

Before natalizumab discontinuation, the mean magnetization transfer ratio value of the gadolinium-enhancing lesions was 31%; at month 3, the mean value had dropped to 19%. “This is a pretty impressive decline, something telling us there might be some fairly intense inflammatory injury on these sites,” Dr. Khan said.

Despite the “alarming” scans, Dr. Khan said, the patients did not show corresponding clinical deterioration. Their mean Expanded Disability Status Scale (EDSS) was 3.2 at discontinuation and did not increase significantly by 3 months.

By 9 months, however, the scans had almost universally improved. The mean number of T2, T1, and gadolinium-enhancing lesions had dropped and were not significantly different from the number of lesions seen at baseline.

Clinically, the patients remained stable, Dr. Khan said. Their mean EDSS at 9 months was 4.0—not significantly worse than it was at natalizumab discontinuation. The mean relapse rate was also not significantly different.

The phenomenon is probably a reaction to the sudden resurgence of lymphocytes into the brain.

Source DR. KHAN

Major Finding: Abrupt discontinuation of natalizumab coincided with a surge in gadolinium-enhancing lesions on MRI that mostly resolved by 9 months without any clinical deterioration.

Data Source: Case series of 11 patients who had received natalizumab infusions before abruptly discontinuing the therapy

Disclosures: Dr. Khan said the study was independently funded and he did not have any financial declarations to make.

BANGKOK, THAILAND — Patients with multiple sclerosis who abruptly discontinue natalizumab treatment may develop a sudden surge in the number of gadolinium-enhancing lesions apparent on imaging, which seems to resolve by 9 months.

The phenomenon is probably a reaction to the sudden resurgence of lymphocytes into the brain—a central nervous system form of immune reconstitution inflammatory syndrome, Dr. Omar Khan said at the World Congress of Neurology.

Although the dramatic imaging changes aren't accompanied by clinical deterioration, about 22% of the lesions did develop into nonenhancing T1 hypointensities, said Dr. Khan, director of the Wayne State University Multiple Sclerosis Clinical Research Center and Radiology Image Analysis Laboratory, Detroit. “Some patients may accumulate a lot of irreversible neuronal damage in this short period of time. And although it's too soon to know for sure, my gut feeling is that over 3 or 4 years, there might be some consequences.”

Dr. Khan presented a case series of 11 patients with MS who had received natalizumab infusions before stopping the treatment abruptly. The reasons for discontinuation included infusion site reactions, the development of neutralizing antibodies, changes in insurance coverage, and worries about developing progressive multifocal leukoencephalopathy.

The patients' mean age was 36 years. They had undergone a mean of 13 natalizumab infusions, although that number ranged from 8 to 21. Before taking natalizumab, their mean relapse rate was 1.6/year; the mean relapse rate at discontinuation of the drug was 0.1/year. All patients were negative for John Cunningham (JC) virus.

Before beginning natalizumab, the patients had a mean of 12 T2 lesions, two T1 lesions and 20 gadolinium-enhancing lesions on MRI. Three months after stopping the drug, the numbers of lesions increased significantly, to 17 T2 lesions, 13 T1 lesions, and 137 gadolinium-enhancing lesions. Overall, 93 of the lesions appeared in brain areas that were previously normal-appearing on imaging.

Before natalizumab discontinuation, the mean magnetization transfer ratio value of the gadolinium-enhancing lesions was 31%; at month 3, the mean value had dropped to 19%. “This is a pretty impressive decline, something telling us there might be some fairly intense inflammatory injury on these sites,” Dr. Khan said.

Despite the “alarming” scans, Dr. Khan said, the patients did not show corresponding clinical deterioration. Their mean Expanded Disability Status Scale (EDSS) was 3.2 at discontinuation and did not increase significantly by 3 months.

By 9 months, however, the scans had almost universally improved. The mean number of T2, T1, and gadolinium-enhancing lesions had dropped and were not significantly different from the number of lesions seen at baseline.

Clinically, the patients remained stable, Dr. Khan said. Their mean EDSS at 9 months was 4.0—not significantly worse than it was at natalizumab discontinuation. The mean relapse rate was also not significantly different.

The phenomenon is probably a reaction to the sudden resurgence of lymphocytes into the brain.

Source DR. KHAN

Major Finding: Abrupt discontinuation of natalizumab coincided with a surge in gadolinium-enhancing lesions on MRI that mostly resolved by 9 months without any clinical deterioration.

Data Source: Case series of 11 patients who had received natalizumab infusions before abruptly discontinuing the therapy

Disclosures: Dr. Khan said the study was independently funded and he did not have any financial declarations to make.

BANGKOK, THAILAND — Patients with multiple sclerosis who abruptly discontinue natalizumab treatment may develop a sudden surge in the number of gadolinium-enhancing lesions apparent on imaging, which seems to resolve by 9 months.

The phenomenon is probably a reaction to the sudden resurgence of lymphocytes into the brain—a central nervous system form of immune reconstitution inflammatory syndrome, Dr. Omar Khan said at the World Congress of Neurology.

Although the dramatic imaging changes aren't accompanied by clinical deterioration, about 22% of the lesions did develop into nonenhancing T1 hypointensities, said Dr. Khan, director of the Wayne State University Multiple Sclerosis Clinical Research Center and Radiology Image Analysis Laboratory, Detroit. “Some patients may accumulate a lot of irreversible neuronal damage in this short period of time. And although it's too soon to know for sure, my gut feeling is that over 3 or 4 years, there might be some consequences.”

Dr. Khan presented a case series of 11 patients with MS who had received natalizumab infusions before stopping the treatment abruptly. The reasons for discontinuation included infusion site reactions, the development of neutralizing antibodies, changes in insurance coverage, and worries about developing progressive multifocal leukoencephalopathy.

The patients' mean age was 36 years. They had undergone a mean of 13 natalizumab infusions, although that number ranged from 8 to 21. Before taking natalizumab, their mean relapse rate was 1.6/year; the mean relapse rate at discontinuation of the drug was 0.1/year. All patients were negative for John Cunningham (JC) virus.

Before beginning natalizumab, the patients had a mean of 12 T2 lesions, two T1 lesions and 20 gadolinium-enhancing lesions on MRI. Three months after stopping the drug, the numbers of lesions increased significantly, to 17 T2 lesions, 13 T1 lesions, and 137 gadolinium-enhancing lesions. Overall, 93 of the lesions appeared in brain areas that were previously normal-appearing on imaging.

Before natalizumab discontinuation, the mean magnetization transfer ratio value of the gadolinium-enhancing lesions was 31%; at month 3, the mean value had dropped to 19%. “This is a pretty impressive decline, something telling us there might be some fairly intense inflammatory injury on these sites,” Dr. Khan said.

Despite the “alarming” scans, Dr. Khan said, the patients did not show corresponding clinical deterioration. Their mean Expanded Disability Status Scale (EDSS) was 3.2 at discontinuation and did not increase significantly by 3 months.

By 9 months, however, the scans had almost universally improved. The mean number of T2, T1, and gadolinium-enhancing lesions had dropped and were not significantly different from the number of lesions seen at baseline.

Clinically, the patients remained stable, Dr. Khan said. Their mean EDSS at 9 months was 4.0—not significantly worse than it was at natalizumab discontinuation. The mean relapse rate was also not significantly different.

The phenomenon is probably a reaction to the sudden resurgence of lymphocytes into the brain.

Source DR. KHAN

BANGKOK, THAILAND — Serum levels of N-acetyl aspartate are significantly higher among patients with relapsing-remitting multiple sclerosis and clinical syndromes suggestive of MS than they are in patients with neuromyelitis optica, and might be a valid biomarker to help distinguish the disorders.

In her study of 176 subjects, Dr. Carla Tortorella found that serum N-acetyl aspartate (NAA) levels were about 14 times higher in those with MS or a clinically isolated syndrome suggestive of MS (CIS) than they were in those with neuromyelitis optica (NMO). In fact, said Dr. Tortorella of the University of Bari, Italy, levels in NMO patients were the same as they were in age-matched healthy controls.

NAA is normally synthesized in neural mitochondria and leaves the cell by several methods, Dr. Tortorella said at the World Congress of Neurology: passing from neurons to oligodendrocytes where it is catabolized; passing through the astrocytes into the extracellular space and thus into the bloodstream; and passing into the cerebrospinal fluid. This process is abnormal in patients with MS, leading to increased serum NAA levels, but no studies have compared these levels in patients with MS and those with NMO.

Dr. Tortorella examined serum and CSF levels of NAA in 48 patients with relapsing-remitting MS, 20 with CIS, and 32 with NMO. She also included 76 age-matched healthy controls for comparison.

There were some baseline differences between the groups. Those with NMO were older (median 43 years) than those with CIS (28 years) or MS (38 years). Disease duration was also different: CIS, 6 months; MS, 6 years; NMO, 5 years.

The Expanded Disability Status Scale score was 1.5 in the CIS group, 2 in the MS group, and 4.6 in the NMO group. None of the MS or CIS patients were taking disease-modifying drugs, while 10 of the NMO patients were taking immunosuppressants.

All patients submitted serum NAA samples. The levels were similarly high in those with CIS and MS (1.7 mM/L in each group). These were significantly higher than the levels found in those with NMO and among healthy controls (0.12 mM/L each).

While all of the MS and CIS patients had CSF levels available for testing, only eight of the NMO patients did, and there were no CSF samples from healthy controls. “Nevertheless, the CSF NAA levels were markedly and consistently higher in the CIS and MS patients [0.68 and 0.76 mM/L] than they were in the NMO patients [0.05 mM/L],” Dr. Tortorella said.

She found no significant association between NAA levels and age, disease duration, or disease activity. However, among those with MS, she found a significant correlation between increasing NAA levels and worsening Expanded Disability Status Scale scores.

Because the correlation between serum NAA and MS is so much stronger than it is with NMO, Dr. Tortorella suggested that NAA might be a useful way not only to help distinguish between the disorders but to measure the progression of MS, particularly in the early phase of the disease.

The findings make sense in light of the pathology of the various disorders, she said. “One theory is that NAA is higher in MS and CIS because there is more extensive and less focal impairment than there is in NMO, suggesting axonal damage that extends beyond the enhancing lesion. There also could be a defective NAA metabolism in the oligodendrocytes, which are really damaged in MS.”

Dr. Tortorella did not have any conflicts of interest to declare.

BANGKOK, THAILAND — Serum levels of N-acetyl aspartate are significantly higher among patients with relapsing-remitting multiple sclerosis and clinical syndromes suggestive of MS than they are in patients with neuromyelitis optica, and might be a valid biomarker to help distinguish the disorders.

In her study of 176 subjects, Dr. Carla Tortorella found that serum N-acetyl aspartate (NAA) levels were about 14 times higher in those with MS or a clinically isolated syndrome suggestive of MS (CIS) than they were in those with neuromyelitis optica (NMO). In fact, said Dr. Tortorella of the University of Bari, Italy, levels in NMO patients were the same as they were in age-matched healthy controls.

NAA is normally synthesized in neural mitochondria and leaves the cell by several methods, Dr. Tortorella said at the World Congress of Neurology: passing from neurons to oligodendrocytes where it is catabolized; passing through the astrocytes into the extracellular space and thus into the bloodstream; and passing into the cerebrospinal fluid. This process is abnormal in patients with MS, leading to increased serum NAA levels, but no studies have compared these levels in patients with MS and those with NMO.

Dr. Tortorella examined serum and CSF levels of NAA in 48 patients with relapsing-remitting MS, 20 with CIS, and 32 with NMO. She also included 76 age-matched healthy controls for comparison.

There were some baseline differences between the groups. Those with NMO were older (median 43 years) than those with CIS (28 years) or MS (38 years). Disease duration was also different: CIS, 6 months; MS, 6 years; NMO, 5 years.

The Expanded Disability Status Scale score was 1.5 in the CIS group, 2 in the MS group, and 4.6 in the NMO group. None of the MS or CIS patients were taking disease-modifying drugs, while 10 of the NMO patients were taking immunosuppressants.

All patients submitted serum NAA samples. The levels were similarly high in those with CIS and MS (1.7 mM/L in each group). These were significantly higher than the levels found in those with NMO and among healthy controls (0.12 mM/L each).

While all of the MS and CIS patients had CSF levels available for testing, only eight of the NMO patients did, and there were no CSF samples from healthy controls. “Nevertheless, the CSF NAA levels were markedly and consistently higher in the CIS and MS patients [0.68 and 0.76 mM/L] than they were in the NMO patients [0.05 mM/L],” Dr. Tortorella said.

She found no significant association between NAA levels and age, disease duration, or disease activity. However, among those with MS, she found a significant correlation between increasing NAA levels and worsening Expanded Disability Status Scale scores.

Because the correlation between serum NAA and MS is so much stronger than it is with NMO, Dr. Tortorella suggested that NAA might be a useful way not only to help distinguish between the disorders but to measure the progression of MS, particularly in the early phase of the disease.

The findings make sense in light of the pathology of the various disorders, she said. “One theory is that NAA is higher in MS and CIS because there is more extensive and less focal impairment than there is in NMO, suggesting axonal damage that extends beyond the enhancing lesion. There also could be a defective NAA metabolism in the oligodendrocytes, which are really damaged in MS.”

Dr. Tortorella did not have any conflicts of interest to declare.

BANGKOK, THAILAND — Serum levels of N-acetyl aspartate are significantly higher among patients with relapsing-remitting multiple sclerosis and clinical syndromes suggestive of MS than they are in patients with neuromyelitis optica, and might be a valid biomarker to help distinguish the disorders.

In her study of 176 subjects, Dr. Carla Tortorella found that serum N-acetyl aspartate (NAA) levels were about 14 times higher in those with MS or a clinically isolated syndrome suggestive of MS (CIS) than they were in those with neuromyelitis optica (NMO). In fact, said Dr. Tortorella of the University of Bari, Italy, levels in NMO patients were the same as they were in age-matched healthy controls.

NAA is normally synthesized in neural mitochondria and leaves the cell by several methods, Dr. Tortorella said at the World Congress of Neurology: passing from neurons to oligodendrocytes where it is catabolized; passing through the astrocytes into the extracellular space and thus into the bloodstream; and passing into the cerebrospinal fluid. This process is abnormal in patients with MS, leading to increased serum NAA levels, but no studies have compared these levels in patients with MS and those with NMO.

Dr. Tortorella examined serum and CSF levels of NAA in 48 patients with relapsing-remitting MS, 20 with CIS, and 32 with NMO. She also included 76 age-matched healthy controls for comparison.

There were some baseline differences between the groups. Those with NMO were older (median 43 years) than those with CIS (28 years) or MS (38 years). Disease duration was also different: CIS, 6 months; MS, 6 years; NMO, 5 years.

The Expanded Disability Status Scale score was 1.5 in the CIS group, 2 in the MS group, and 4.6 in the NMO group. None of the MS or CIS patients were taking disease-modifying drugs, while 10 of the NMO patients were taking immunosuppressants.

All patients submitted serum NAA samples. The levels were similarly high in those with CIS and MS (1.7 mM/L in each group). These were significantly higher than the levels found in those with NMO and among healthy controls (0.12 mM/L each).

While all of the MS and CIS patients had CSF levels available for testing, only eight of the NMO patients did, and there were no CSF samples from healthy controls. “Nevertheless, the CSF NAA levels were markedly and consistently higher in the CIS and MS patients [0.68 and 0.76 mM/L] than they were in the NMO patients [0.05 mM/L],” Dr. Tortorella said.

She found no significant association between NAA levels and age, disease duration, or disease activity. However, among those with MS, she found a significant correlation between increasing NAA levels and worsening Expanded Disability Status Scale scores.

Because the correlation between serum NAA and MS is so much stronger than it is with NMO, Dr. Tortorella suggested that NAA might be a useful way not only to help distinguish between the disorders but to measure the progression of MS, particularly in the early phase of the disease.

The findings make sense in light of the pathology of the various disorders, she said. “One theory is that NAA is higher in MS and CIS because there is more extensive and less focal impairment than there is in NMO, suggesting axonal damage that extends beyond the enhancing lesion. There also could be a defective NAA metabolism in the oligodendrocytes, which are really damaged in MS.”

Dr. Tortorella did not have any conflicts of interest to declare.

25th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), Dusseldorf, Germany

Fewer Injection Site Reactions Occur in Patients Using Interferon Beta-1a IM
Data from an observational phase IV study of 499 patients—the Swiss MS Skin Project—showed that patients with multiple sclerosis (MS) taking interferon beta-1a IM reported significantly fewer injection site reactions, compared with patients who took interferon beta-1b, glatiramer acetate, or interferon beta-1a. The study also found that patients taking interferon beta-1a IM were less likely to have missed a dose due to an injection site reaction in the four weeks prior to first assessment than those patients on other interferon therapies.

“This study showed that treatment with interferon beta-1a IM leads to fewer injection site reactions, which is an important factor in improving compliance,” said Karsten Beer, lead investigator for the study and a private neurologist in Wil, Switzerland. “As the only once-weekly injection treatment, interferon beta-1a IM offers people with relapsing MS an easy-to-use and highly effective treatment option. Convenience of an MS therapy is an important consideration for patients, as they do not want a therapy that will interfere with their daily lives.”

The Swiss MS Skin Project was designed to determine the frequency of injection site reactions, including skin necrosis and lipoatrophy, in patients taking interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a. Injection site reactions are believed to reduce treatment compliance among patients. The study enrolled nearly 500 patients on interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a for a minimum of two years (mean treatment duration, 5.9 years) and followed patients for one year.

At the first assessment, significantly fewer patients who took interferon beta-1a IM experienced injection site reactions (13.4% vs 57.7% of those who used interferon beta-1b, 30.4% for glatiramer acetate, and 67.9% for interferon beta-1a); necrosis (0% vs 5.7% for interferon beta-1b, 0% for glatiramer acetate, and 6.0% for interferon beta-1a); and lipoatrophy (1.2 % vs 8.9% for interferon beta-1b, 13.0% for glatiramer acetate, and 10.3% for interferon beta-1a).

No patients who used interferon beta-1a IM missed a dose in the four weeks prior to first assessment due to injection site reactions (vs 5.7% of patients using interferon beta-1b, 4.3% for glatiramer acetate, and 7.1% for interferon beta-1a). These percentages were statistically significant, compared with use of interferon beta-1b and interferon beta-1a. In addition, significantly more patients remained on interferon beta-1a IM throughout the one-year trial (86.6% vs 79.7% of subjects who used interferon beta-1b, 60.9% for glatiramer acetate, and 83.2% for interferon beta-1a) than on any other treatment.

Patients Taking Natalizumab Report Improvement in Physical and Psychologic Well-Being
Patients with multiple sclerosis (MS) taking natalizumab experienced an improvement in both their physical function and psychologic well-being, according to six-month results of an ongoing, one-year longitudinal, observational, patient-reported outcomes study. The study, which was the first to assess patient experiences with natalizumab in usual-care settings, found that patients who used natalizumab reported an improvement in their overall quality of life.

“The symptoms that a patient with MS deals with on a daily basis result in significant psychologic and physical effects that can adversely impact their quality of life,” said William Stuart, MD, Medical Director of the Multiple Sclerosis Center of Atlanta. “In a previous pivotal trial, natalizumab not only showed a reduction in relapse rates and disability progression, but also improved quality of life. Results from this observational study further demonstrate the impact of natalizumab on improving MS patients’ well-being as reported by patients who live with this disease every day.”

The trial assessed health outcomes from patients’ perspectives before starting natalizumab and after the third, sixth, and 12th infusions of the drug. A majority of the patients in the study are female (76.3%), with a mean age of 46.6 and mean disease duration of 10 years.

After six natalizumab infusions, patients reported statistically significant improvement in disease-specific quality of life, measured with use of the MS Impact Scale-29 (MSIS-29), which assesses the physical impact of MS in terms of mobility and self-care, as well as the psychologic impact of MS in terms of anxiety/depression, with lower scores indicating better quality of life. Patients also reported statistically significant improvement in general health-related quality of life, as measured by the 12-item Short Form Scale (SF-12) health survey, which assesses the physical and mental health, with higher scores indicating better quality of life.

Both scales assess patient experience of the physical and psychologic aspects of quality of life. For the MSIS-29 subscales, statistically significant improvements were observed over time for both the physical (baseline, 46.87; third infusion, 39.60; sixth infusion, 39.27) and psychologic (baseline, 41.56; third infusion, 33.77; sixth infusion, 33.20) impact scores.

SF-12 physical component summary score (baseline, 34.20; third infusion, 36.05; sixth infusion, 36.34) and the SF-12 mental component summary score (baseline, 43.25; third infusion, 47.35; sixth infusion, 47.92) showed statistically significant improvements over time.
[Editor’s note: For more information on natalizumab, please see a related news story and commentary on page 5.]

Genetic Targets for Potential MS Therapies
Two genes in mice were associated with good CNS repair in multiple sclerosis (MS). The findings may help researchers develop more effective therapies and predict outcomes for patients with MS.

“Most MS genetic studies have looked at disease susceptibility—or why some people get MS and others do not,” said Allan Bieber, PhD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota. “This study asked, among those who have MS, why some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome.”

Dr. Bieber and a team of Mayo Clinic researchers used two different strains of mice with a chronic, progressive MS-like disease. One strain of mice progressed to paralysis and death. The other strain underwent the initial damage induction phase of the disease and then had spontaneous repair of the damage to the CNS and retained most neurologic function. Using the genetic mapping techniques that are available for mice, the team mapped two strong genetic determinants of good disease outcome.

“It’s possible that the identification of these genes may provide the first important clue as to why some patients with MS do well, while others do not,” said Dr. Bieber. “The genetic data indicate that good CNS repair results from stimulation of one genetic pathway and inhibition of another genetic pathway. While we’re still in the early stages of this research, it could eventually lead to the development of useful therapies that stimulate or inhibit these genetic pathways in patients with MS.”

According to Dr. Bieber, the research suggests that there may be a small number of strong genetic determinants for CNS repair following demyelinating disease, rather than a larger number of weak determinants.

“If that’s true, it may be possible to map the most important genetic determinants of CNS repair in patients with MS and define a reparative genotype that could predict patients’ outcomes,” said Moses Rodriguez, MD, Professor of Neurology and Director of the Mayo Clinic’s Center for Multiple Sclerosis and Central Nervous System Demyelinating Diseases Research and Therapeutics. “Such a diagnostic tool would be a great benefit to patients with MS and is consistent with the concepts of individualized medicine.”

Research Supports the Importance of Early Treatment in Patients With MS
Findings from two observational studies—CogniCIS and CogniMS—revealed that depression and fatigue occur alongside cognitive deficits, even early in the disease. Data from these studies showed that relatives were able to detect even minor changes in cognitive performance at an early stage of the disease, which the patients themselves did not report.

“Cognitive impairment in patients with multiple sclerosis (MS) is not sufficiently recognized, in spite of the significant negative impact it can have on patients’ lives,” said Dawn Langdon, PhD, Neuropsychology Lead and Reader in Neuropsychology, Royal Holloway, University of London, UK, and lead investigator of CogniCIS and CogniMS. “These studies will help us construct a more complete picture of the development and impact of cognitive decline in early MS. Such findings, added to the existing evidence, will have important implications for physicians when making management decisions.”

The CogniCIS study collected cognitive and psychosocial data from 394 patients with clinically isolated syndrome (CIS). A subset of 130 European patients with CIS and 60 of their relatives completed the MS Neuropsychological Questionnaire (MSNQ), which asks about cognitive difficulties. Preliminary results presented showed that scores on the MSNQ from patients with CIS and their relatives correlated more with the patients’ level of depression, fatigue, and quality of life rather than performance in cognitive tests.

The CogniMS study included psychosocial data from 1,509 patients with early MS. A subset of 274 patients and 178 of their relatives completed the MSNQ. According to preliminary findings from the trial, relatives’ reports of the patients’ cognition correlated with some cognitive test scores, obtained by patients; patient self-reported cognitive deficits were not closely related to objective test scores. Similar to results from CogniCIS, the CogniMS findings suggest that self-reported cognitive deficits in an early MS population are not specific to cognition, and are influenced by the patients’ psychologic situation.

25th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), Dusseldorf, Germany

Fewer Injection Site Reactions Occur in Patients Using Interferon Beta-1a IM
Data from an observational phase IV study of 499 patients—the Swiss MS Skin Project—showed that patients with multiple sclerosis (MS) taking interferon beta-1a IM reported significantly fewer injection site reactions, compared with patients who took interferon beta-1b, glatiramer acetate, or interferon beta-1a. The study also found that patients taking interferon beta-1a IM were less likely to have missed a dose due to an injection site reaction in the four weeks prior to first assessment than those patients on other interferon therapies.

“This study showed that treatment with interferon beta-1a IM leads to fewer injection site reactions, which is an important factor in improving compliance,” said Karsten Beer, lead investigator for the study and a private neurologist in Wil, Switzerland. “As the only once-weekly injection treatment, interferon beta-1a IM offers people with relapsing MS an easy-to-use and highly effective treatment option. Convenience of an MS therapy is an important consideration for patients, as they do not want a therapy that will interfere with their daily lives.”

The Swiss MS Skin Project was designed to determine the frequency of injection site reactions, including skin necrosis and lipoatrophy, in patients taking interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a. Injection site reactions are believed to reduce treatment compliance among patients. The study enrolled nearly 500 patients on interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a for a minimum of two years (mean treatment duration, 5.9 years) and followed patients for one year.

At the first assessment, significantly fewer patients who took interferon beta-1a IM experienced injection site reactions (13.4% vs 57.7% of those who used interferon beta-1b, 30.4% for glatiramer acetate, and 67.9% for interferon beta-1a); necrosis (0% vs 5.7% for interferon beta-1b, 0% for glatiramer acetate, and 6.0% for interferon beta-1a); and lipoatrophy (1.2 % vs 8.9% for interferon beta-1b, 13.0% for glatiramer acetate, and 10.3% for interferon beta-1a).

No patients who used interferon beta-1a IM missed a dose in the four weeks prior to first assessment due to injection site reactions (vs 5.7% of patients using interferon beta-1b, 4.3% for glatiramer acetate, and 7.1% for interferon beta-1a). These percentages were statistically significant, compared with use of interferon beta-1b and interferon beta-1a. In addition, significantly more patients remained on interferon beta-1a IM throughout the one-year trial (86.6% vs 79.7% of subjects who used interferon beta-1b, 60.9% for glatiramer acetate, and 83.2% for interferon beta-1a) than on any other treatment.

Patients Taking Natalizumab Report Improvement in Physical and Psychologic Well-Being
Patients with multiple sclerosis (MS) taking natalizumab experienced an improvement in both their physical function and psychologic well-being, according to six-month results of an ongoing, one-year longitudinal, observational, patient-reported outcomes study. The study, which was the first to assess patient experiences with natalizumab in usual-care settings, found that patients who used natalizumab reported an improvement in their overall quality of life.

“The symptoms that a patient with MS deals with on a daily basis result in significant psychologic and physical effects that can adversely impact their quality of life,” said William Stuart, MD, Medical Director of the Multiple Sclerosis Center of Atlanta. “In a previous pivotal trial, natalizumab not only showed a reduction in relapse rates and disability progression, but also improved quality of life. Results from this observational study further demonstrate the impact of natalizumab on improving MS patients’ well-being as reported by patients who live with this disease every day.”

The trial assessed health outcomes from patients’ perspectives before starting natalizumab and after the third, sixth, and 12th infusions of the drug. A majority of the patients in the study are female (76.3%), with a mean age of 46.6 and mean disease duration of 10 years.

After six natalizumab infusions, patients reported statistically significant improvement in disease-specific quality of life, measured with use of the MS Impact Scale-29 (MSIS-29), which assesses the physical impact of MS in terms of mobility and self-care, as well as the psychologic impact of MS in terms of anxiety/depression, with lower scores indicating better quality of life. Patients also reported statistically significant improvement in general health-related quality of life, as measured by the 12-item Short Form Scale (SF-12) health survey, which assesses the physical and mental health, with higher scores indicating better quality of life.

Both scales assess patient experience of the physical and psychologic aspects of quality of life. For the MSIS-29 subscales, statistically significant improvements were observed over time for both the physical (baseline, 46.87; third infusion, 39.60; sixth infusion, 39.27) and psychologic (baseline, 41.56; third infusion, 33.77; sixth infusion, 33.20) impact scores.

SF-12 physical component summary score (baseline, 34.20; third infusion, 36.05; sixth infusion, 36.34) and the SF-12 mental component summary score (baseline, 43.25; third infusion, 47.35; sixth infusion, 47.92) showed statistically significant improvements over time.
[Editor’s note: For more information on natalizumab, please see a related news story and commentary on page 5.]

Genetic Targets for Potential MS Therapies
Two genes in mice were associated with good CNS repair in multiple sclerosis (MS). The findings may help researchers develop more effective therapies and predict outcomes for patients with MS.

“Most MS genetic studies have looked at disease susceptibility—or why some people get MS and others do not,” said Allan Bieber, PhD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota. “This study asked, among those who have MS, why some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome.”

Dr. Bieber and a team of Mayo Clinic researchers used two different strains of mice with a chronic, progressive MS-like disease. One strain of mice progressed to paralysis and death. The other strain underwent the initial damage induction phase of the disease and then had spontaneous repair of the damage to the CNS and retained most neurologic function. Using the genetic mapping techniques that are available for mice, the team mapped two strong genetic determinants of good disease outcome.

“It’s possible that the identification of these genes may provide the first important clue as to why some patients with MS do well, while others do not,” said Dr. Bieber. “The genetic data indicate that good CNS repair results from stimulation of one genetic pathway and inhibition of another genetic pathway. While we’re still in the early stages of this research, it could eventually lead to the development of useful therapies that stimulate or inhibit these genetic pathways in patients with MS.”

According to Dr. Bieber, the research suggests that there may be a small number of strong genetic determinants for CNS repair following demyelinating disease, rather than a larger number of weak determinants.

“If that’s true, it may be possible to map the most important genetic determinants of CNS repair in patients with MS and define a reparative genotype that could predict patients’ outcomes,” said Moses Rodriguez, MD, Professor of Neurology and Director of the Mayo Clinic’s Center for Multiple Sclerosis and Central Nervous System Demyelinating Diseases Research and Therapeutics. “Such a diagnostic tool would be a great benefit to patients with MS and is consistent with the concepts of individualized medicine.”

Research Supports the Importance of Early Treatment in Patients With MS
Findings from two observational studies—CogniCIS and CogniMS—revealed that depression and fatigue occur alongside cognitive deficits, even early in the disease. Data from these studies showed that relatives were able to detect even minor changes in cognitive performance at an early stage of the disease, which the patients themselves did not report.

“Cognitive impairment in patients with multiple sclerosis (MS) is not sufficiently recognized, in spite of the significant negative impact it can have on patients’ lives,” said Dawn Langdon, PhD, Neuropsychology Lead and Reader in Neuropsychology, Royal Holloway, University of London, UK, and lead investigator of CogniCIS and CogniMS. “These studies will help us construct a more complete picture of the development and impact of cognitive decline in early MS. Such findings, added to the existing evidence, will have important implications for physicians when making management decisions.”

The CogniCIS study collected cognitive and psychosocial data from 394 patients with clinically isolated syndrome (CIS). A subset of 130 European patients with CIS and 60 of their relatives completed the MS Neuropsychological Questionnaire (MSNQ), which asks about cognitive difficulties. Preliminary results presented showed that scores on the MSNQ from patients with CIS and their relatives correlated more with the patients’ level of depression, fatigue, and quality of life rather than performance in cognitive tests.

The CogniMS study included psychosocial data from 1,509 patients with early MS. A subset of 274 patients and 178 of their relatives completed the MSNQ. According to preliminary findings from the trial, relatives’ reports of the patients’ cognition correlated with some cognitive test scores, obtained by patients; patient self-reported cognitive deficits were not closely related to objective test scores. Similar to results from CogniCIS, the CogniMS findings suggest that self-reported cognitive deficits in an early MS population are not specific to cognition, and are influenced by the patients’ psychologic situation.

25th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), Dusseldorf, Germany

Fewer Injection Site Reactions Occur in Patients Using Interferon Beta-1a IM
Data from an observational phase IV study of 499 patients—the Swiss MS Skin Project—showed that patients with multiple sclerosis (MS) taking interferon beta-1a IM reported significantly fewer injection site reactions, compared with patients who took interferon beta-1b, glatiramer acetate, or interferon beta-1a. The study also found that patients taking interferon beta-1a IM were less likely to have missed a dose due to an injection site reaction in the four weeks prior to first assessment than those patients on other interferon therapies.

“This study showed that treatment with interferon beta-1a IM leads to fewer injection site reactions, which is an important factor in improving compliance,” said Karsten Beer, lead investigator for the study and a private neurologist in Wil, Switzerland. “As the only once-weekly injection treatment, interferon beta-1a IM offers people with relapsing MS an easy-to-use and highly effective treatment option. Convenience of an MS therapy is an important consideration for patients, as they do not want a therapy that will interfere with their daily lives.”

The Swiss MS Skin Project was designed to determine the frequency of injection site reactions, including skin necrosis and lipoatrophy, in patients taking interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a. Injection site reactions are believed to reduce treatment compliance among patients. The study enrolled nearly 500 patients on interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a for a minimum of two years (mean treatment duration, 5.9 years) and followed patients for one year.

At the first assessment, significantly fewer patients who took interferon beta-1a IM experienced injection site reactions (13.4% vs 57.7% of those who used interferon beta-1b, 30.4% for glatiramer acetate, and 67.9% for interferon beta-1a); necrosis (0% vs 5.7% for interferon beta-1b, 0% for glatiramer acetate, and 6.0% for interferon beta-1a); and lipoatrophy (1.2 % vs 8.9% for interferon beta-1b, 13.0% for glatiramer acetate, and 10.3% for interferon beta-1a).

No patients who used interferon beta-1a IM missed a dose in the four weeks prior to first assessment due to injection site reactions (vs 5.7% of patients using interferon beta-1b, 4.3% for glatiramer acetate, and 7.1% for interferon beta-1a). These percentages were statistically significant, compared with use of interferon beta-1b and interferon beta-1a. In addition, significantly more patients remained on interferon beta-1a IM throughout the one-year trial (86.6% vs 79.7% of subjects who used interferon beta-1b, 60.9% for glatiramer acetate, and 83.2% for interferon beta-1a) than on any other treatment.

Patients Taking Natalizumab Report Improvement in Physical and Psychologic Well-Being
Patients with multiple sclerosis (MS) taking natalizumab experienced an improvement in both their physical function and psychologic well-being, according to six-month results of an ongoing, one-year longitudinal, observational, patient-reported outcomes study. The study, which was the first to assess patient experiences with natalizumab in usual-care settings, found that patients who used natalizumab reported an improvement in their overall quality of life.

“The symptoms that a patient with MS deals with on a daily basis result in significant psychologic and physical effects that can adversely impact their quality of life,” said William Stuart, MD, Medical Director of the Multiple Sclerosis Center of Atlanta. “In a previous pivotal trial, natalizumab not only showed a reduction in relapse rates and disability progression, but also improved quality of life. Results from this observational study further demonstrate the impact of natalizumab on improving MS patients’ well-being as reported by patients who live with this disease every day.”

The trial assessed health outcomes from patients’ perspectives before starting natalizumab and after the third, sixth, and 12th infusions of the drug. A majority of the patients in the study are female (76.3%), with a mean age of 46.6 and mean disease duration of 10 years.

After six natalizumab infusions, patients reported statistically significant improvement in disease-specific quality of life, measured with use of the MS Impact Scale-29 (MSIS-29), which assesses the physical impact of MS in terms of mobility and self-care, as well as the psychologic impact of MS in terms of anxiety/depression, with lower scores indicating better quality of life. Patients also reported statistically significant improvement in general health-related quality of life, as measured by the 12-item Short Form Scale (SF-12) health survey, which assesses the physical and mental health, with higher scores indicating better quality of life.

Both scales assess patient experience of the physical and psychologic aspects of quality of life. For the MSIS-29 subscales, statistically significant improvements were observed over time for both the physical (baseline, 46.87; third infusion, 39.60; sixth infusion, 39.27) and psychologic (baseline, 41.56; third infusion, 33.77; sixth infusion, 33.20) impact scores.

SF-12 physical component summary score (baseline, 34.20; third infusion, 36.05; sixth infusion, 36.34) and the SF-12 mental component summary score (baseline, 43.25; third infusion, 47.35; sixth infusion, 47.92) showed statistically significant improvements over time.
[Editor’s note: For more information on natalizumab, please see a related news story and commentary on page 5.]

Genetic Targets for Potential MS Therapies
Two genes in mice were associated with good CNS repair in multiple sclerosis (MS). The findings may help researchers develop more effective therapies and predict outcomes for patients with MS.

“Most MS genetic studies have looked at disease susceptibility—or why some people get MS and others do not,” said Allan Bieber, PhD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota. “This study asked, among those who have MS, why some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome.”

Dr. Bieber and a team of Mayo Clinic researchers used two different strains of mice with a chronic, progressive MS-like disease. One strain of mice progressed to paralysis and death. The other strain underwent the initial damage induction phase of the disease and then had spontaneous repair of the damage to the CNS and retained most neurologic function. Using the genetic mapping techniques that are available for mice, the team mapped two strong genetic determinants of good disease outcome.

“It’s possible that the identification of these genes may provide the first important clue as to why some patients with MS do well, while others do not,” said Dr. Bieber. “The genetic data indicate that good CNS repair results from stimulation of one genetic pathway and inhibition of another genetic pathway. While we’re still in the early stages of this research, it could eventually lead to the development of useful therapies that stimulate or inhibit these genetic pathways in patients with MS.”

According to Dr. Bieber, the research suggests that there may be a small number of strong genetic determinants for CNS repair following demyelinating disease, rather than a larger number of weak determinants.

“If that’s true, it may be possible to map the most important genetic determinants of CNS repair in patients with MS and define a reparative genotype that could predict patients’ outcomes,” said Moses Rodriguez, MD, Professor of Neurology and Director of the Mayo Clinic’s Center for Multiple Sclerosis and Central Nervous System Demyelinating Diseases Research and Therapeutics. “Such a diagnostic tool would be a great benefit to patients with MS and is consistent with the concepts of individualized medicine.”

Research Supports the Importance of Early Treatment in Patients With MS
Findings from two observational studies—CogniCIS and CogniMS—revealed that depression and fatigue occur alongside cognitive deficits, even early in the disease. Data from these studies showed that relatives were able to detect even minor changes in cognitive performance at an early stage of the disease, which the patients themselves did not report.

“Cognitive impairment in patients with multiple sclerosis (MS) is not sufficiently recognized, in spite of the significant negative impact it can have on patients’ lives,” said Dawn Langdon, PhD, Neuropsychology Lead and Reader in Neuropsychology, Royal Holloway, University of London, UK, and lead investigator of CogniCIS and CogniMS. “These studies will help us construct a more complete picture of the development and impact of cognitive decline in early MS. Such findings, added to the existing evidence, will have important implications for physicians when making management decisions.”

The CogniCIS study collected cognitive and psychosocial data from 394 patients with clinically isolated syndrome (CIS). A subset of 130 European patients with CIS and 60 of their relatives completed the MS Neuropsychological Questionnaire (MSNQ), which asks about cognitive difficulties. Preliminary results presented showed that scores on the MSNQ from patients with CIS and their relatives correlated more with the patients’ level of depression, fatigue, and quality of life rather than performance in cognitive tests.

The CogniMS study included psychosocial data from 1,509 patients with early MS. A subset of 274 patients and 178 of their relatives completed the MSNQ. According to preliminary findings from the trial, relatives’ reports of the patients’ cognition correlated with some cognitive test scores, obtained by patients; patient self-reported cognitive deficits were not closely related to objective test scores. Similar to results from CogniCIS, the CogniMS findings suggest that self-reported cognitive deficits in an early MS population are not specific to cognition, and are influenced by the patients’ psychologic situation.