ICYMI Multiple Sclerosis

Demographic and Clinical Factors Influence Survival of Patients With Parkinson’s Disease
Clinical conditions such as dementia and demographic factors such as race, sex, and age influence the survival rates of patients with Parkinson’s disease, according to research published in the January 2 issue of Archives of Neurology.

To determine the life expectancy of patients with Parkinson’s disease in the United States and identify factors that influence survival, Allison W. Willis, MD, of the Department of Neurology at the Washington University School of Medicine in St. Louis, and colleagues conducted a retrospective cohort study of 138,728 Medicare beneficiaries with incident Parkinson’s disease. Patients were 65 and older, and the population included 65,423 men and 73,305 women. The researchers identified the patients in 2002 and followed up through 2008.

The main outcome measures were confounder-adjusted six-year risk of death as influenced by three groups of factors, including race, sex, and age at diagnosis; geography and environmental factors; and clinical conditions. Dr. Willis examined hospitalization diagnoses in patients with terminal Parkinson’s disease and compared disease mortality with that of other common diseases.

Sixty-four percent of patients with Parkinson’s disease died during the six-year study, and the authors found that “sex and race significantly predicted survival.” Women with Parkinson’s disease had a 26% lower adjusted risk of death than men. African Americans and whites had the two highest crude death rates at 66.4% and 64.6%, respectively. Hispanics had a lower death rate (ie, 55.4%), and Asians had the lowest death rate (50.8%). Survival decreased with age.

Dementia was diagnosed in 69.6% of cases and was associated with a greater likelihood of death. Patients with Parkinson’s disease and dementia had a 28.1% survival rate, while patients without dementia had a 53.9% survival rate. Patients with dementia and Parkinson’s disease were 72% more likely to die during the study, and dementia had the strongest effect on age-adjusted survival among the variables studied, according to the authors.

Survival rates were similar across states, between regions of the country, and by rural or urban classification. However, patients with Parkinson’s disease who lived in urban areas and areas of high industrial metal emissions had a slightly higher adjusted risk of death (19%). Dr. Willis and her colleagues concluded that more research was needed to understand whether environmental exposures influence survival among patients with Parkinson’s disease.
Willis AW, Schootman M, Kung N, et al. Predictors of survival in patients with Parkinson disease. Arch Neurol. 2012 Jan 2; [Epub ahead of print].

Latent Epstein-Barr Virus May Activate Innate Immune Responses in the MS Brain
Latent Epstein-Barr virus (EBV) infection may contribute to neuroinflammation in patients with multiple sclerosis (MS), according to research published in the January 3 issue of Neurology.

A team led by J. S. Tzartos, DPhil, of the Department of Neuropathology, John Radcliffe Hospital, University of Oxford, United Kingdom, studied whether the activation of innate immune responses was associated with the presence of EBV in brains afflicted with MS. The group used immunohistochemistry to analyze 10 samples of white matter postmortem MS and 11 samples of control tissue for the expression of the proinflammatory cytokine interferon α (IFNα). The researchers also analyzed the samples for EBV using EBV-encoded RNA (EBER) in situ hybridization.

Dr. Tzartos and colleagues found overexpression of IFNα in active areas of white matter MS lesions, but not in inactive MS lesions, normal-appearing white matter, or normal brains. The team also found EBERs in areas where IFNα was overexpressed in active MS lesions. EBER+ cells were present in samples taken from CNS lymphoma and stroke cases, but not in other control brains. After transfecting EBERs into human embryonic kidney cells, the researchers found that the former elicited IFNα production in vitro.

“As we found EBER+ cells not only in white matter areas of these active MS lesions, but also CNS lymphoma and two cases of stroke, we conclude that the presence of EBV may not be unique to the MS brain, in contrast to previous findings,” wrote Dr. Tzartos. “Thus, our study casts new light on mechanistic interactions of viral RNAs and innate immune activation in the CNS, and may highlight the propensity of latent viral infections to contribute to neuroinflammation in the CNS, not only in MS, but also in other neuroinflammatory diseases.”

Dr. Tzartos’s findings “revitalize a debate that was heading toward a negative conclusion, that is, EBV-infected B cells are a rare and coincidental finding in MS brains,” wrote Jan D. Lünemann, MD, of the University of Zürich, in an accompanying editorial. An accumulation of EBV-infected B cells in inflammatory CNS lesions, which are rich in B cells, may represent a bystander phenomenon, but “bystanders do not necessarily remain silent and innocent,” wrote Dr. Lünemann.
Tzartos JS, Khan G, Vossenkamper A, et al. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology. 2012;78(1):15–23.
Lünemann JD, Epstein–Barr virus in multiple sclerosis. Neurology. 2012;78(1):11–12.

High Adiponectin Levels May Increase Dementia Risk in Women
Women with elevated plasma adiponectin levels may have an increased risk of developing both all-cause dementia and Alzheimer’s disease, researchers reported in the January 2 online issue of Archives of Neurology.

Thomas M. van Himbergen, PhD, a postdoctoral associate at the Lipid Metabolism Laboratory at Tufts University in Boston, and colleagues examined biomarkers for glucose homeostasis (ie, adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (ie, high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) in a prospective cohort study that included 840 dementia-free participants in the Framingham Heart Study. The participants, 541 of whom were women, had a median age of 76, and the researchers measured subjects’ sera for biomarkers at the 19th biennial examination (1985 to 1988).

During the mean 13-year follow-up period for development of Alzheimer’s disease and all-cause dementia, 159 cases of dementia were identified, including 125 cases of Alzheimer’s disease. To evaluate which biomarkers may contribute to disease development, the researchers used sex-pooled and sex-specific Multivariable Cox Proportional Hazards models to control for other dementia risk factors such as age, education, APOE e4 allele status, plasma docosahexaenoic acid levels, weight change, and BMI.

Plasma insulin, glucose, and glycated albumin levels as well as the inflammatory marker lipoprotein-associated phospholipase A2 were not linked with Alzheimer’s disease or all-cause dementia. Although high-sensitivity C-reactive protein initially seemed to be associated with a lower risk of Alzheimer’s disease and dementia, adjustment for the APOE e4 allele and other factors revealed that the association was not significant. The investigators identified adiponectin as the only factor associated with a higher risk of all-cause dementia and Alzheimer’s disease in women.

Furthermore, women with baseline adiponectin levels greater than the sex-specific median showed a higher risk of all-cause dementia, compared to women with adiponectin values less than the median, even after adjustment for other risk factors.

“It is well established that insulin signaling is dysfunctional in the brains of patients with Alzheimer’s disease, and since adiponectin enhances insulin sensitivity, one would also expect beneficial actions protecting against cognitive decline,” Dr. van Himbergen’s group noted. “Our data, however, indicated that elevated adiponectin level was associated with an increased risk of dementia and Alzheimer’s disease in women.”
van Himbergen TM, Beiser AS, Ai M, et al. Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and Alzheimer disease. Arch Neurol. 2012 Jan 2; [Epub ahead of print].

Demographic and Clinical Factors Influence Survival of Patients With Parkinson’s Disease
Clinical conditions such as dementia and demographic factors such as race, sex, and age influence the survival rates of patients with Parkinson’s disease, according to research published in the January 2 issue of Archives of Neurology.

To determine the life expectancy of patients with Parkinson’s disease in the United States and identify factors that influence survival, Allison W. Willis, MD, of the Department of Neurology at the Washington University School of Medicine in St. Louis, and colleagues conducted a retrospective cohort study of 138,728 Medicare beneficiaries with incident Parkinson’s disease. Patients were 65 and older, and the population included 65,423 men and 73,305 women. The researchers identified the patients in 2002 and followed up through 2008.

The main outcome measures were confounder-adjusted six-year risk of death as influenced by three groups of factors, including race, sex, and age at diagnosis; geography and environmental factors; and clinical conditions. Dr. Willis examined hospitalization diagnoses in patients with terminal Parkinson’s disease and compared disease mortality with that of other common diseases.

Sixty-four percent of patients with Parkinson’s disease died during the six-year study, and the authors found that “sex and race significantly predicted survival.” Women with Parkinson’s disease had a 26% lower adjusted risk of death than men. African Americans and whites had the two highest crude death rates at 66.4% and 64.6%, respectively. Hispanics had a lower death rate (ie, 55.4%), and Asians had the lowest death rate (50.8%). Survival decreased with age.

Dementia was diagnosed in 69.6% of cases and was associated with a greater likelihood of death. Patients with Parkinson’s disease and dementia had a 28.1% survival rate, while patients without dementia had a 53.9% survival rate. Patients with dementia and Parkinson’s disease were 72% more likely to die during the study, and dementia had the strongest effect on age-adjusted survival among the variables studied, according to the authors.

Survival rates were similar across states, between regions of the country, and by rural or urban classification. However, patients with Parkinson’s disease who lived in urban areas and areas of high industrial metal emissions had a slightly higher adjusted risk of death (19%). Dr. Willis and her colleagues concluded that more research was needed to understand whether environmental exposures influence survival among patients with Parkinson’s disease.
Willis AW, Schootman M, Kung N, et al. Predictors of survival in patients with Parkinson disease. Arch Neurol. 2012 Jan 2; [Epub ahead of print].

Latent Epstein-Barr Virus May Activate Innate Immune Responses in the MS Brain
Latent Epstein-Barr virus (EBV) infection may contribute to neuroinflammation in patients with multiple sclerosis (MS), according to research published in the January 3 issue of Neurology.

A team led by J. S. Tzartos, DPhil, of the Department of Neuropathology, John Radcliffe Hospital, University of Oxford, United Kingdom, studied whether the activation of innate immune responses was associated with the presence of EBV in brains afflicted with MS. The group used immunohistochemistry to analyze 10 samples of white matter postmortem MS and 11 samples of control tissue for the expression of the proinflammatory cytokine interferon α (IFNα). The researchers also analyzed the samples for EBV using EBV-encoded RNA (EBER) in situ hybridization.

Dr. Tzartos and colleagues found overexpression of IFNα in active areas of white matter MS lesions, but not in inactive MS lesions, normal-appearing white matter, or normal brains. The team also found EBERs in areas where IFNα was overexpressed in active MS lesions. EBER+ cells were present in samples taken from CNS lymphoma and stroke cases, but not in other control brains. After transfecting EBERs into human embryonic kidney cells, the researchers found that the former elicited IFNα production in vitro.

“As we found EBER+ cells not only in white matter areas of these active MS lesions, but also CNS lymphoma and two cases of stroke, we conclude that the presence of EBV may not be unique to the MS brain, in contrast to previous findings,” wrote Dr. Tzartos. “Thus, our study casts new light on mechanistic interactions of viral RNAs and innate immune activation in the CNS, and may highlight the propensity of latent viral infections to contribute to neuroinflammation in the CNS, not only in MS, but also in other neuroinflammatory diseases.”

Dr. Tzartos’s findings “revitalize a debate that was heading toward a negative conclusion, that is, EBV-infected B cells are a rare and coincidental finding in MS brains,” wrote Jan D. Lünemann, MD, of the University of Zürich, in an accompanying editorial. An accumulation of EBV-infected B cells in inflammatory CNS lesions, which are rich in B cells, may represent a bystander phenomenon, but “bystanders do not necessarily remain silent and innocent,” wrote Dr. Lünemann.
Tzartos JS, Khan G, Vossenkamper A, et al. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology. 2012;78(1):15–23.
Lünemann JD, Epstein–Barr virus in multiple sclerosis. Neurology. 2012;78(1):11–12.

High Adiponectin Levels May Increase Dementia Risk in Women
Women with elevated plasma adiponectin levels may have an increased risk of developing both all-cause dementia and Alzheimer’s disease, researchers reported in the January 2 online issue of Archives of Neurology.

Thomas M. van Himbergen, PhD, a postdoctoral associate at the Lipid Metabolism Laboratory at Tufts University in Boston, and colleagues examined biomarkers for glucose homeostasis (ie, adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (ie, high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) in a prospective cohort study that included 840 dementia-free participants in the Framingham Heart Study. The participants, 541 of whom were women, had a median age of 76, and the researchers measured subjects’ sera for biomarkers at the 19th biennial examination (1985 to 1988).

During the mean 13-year follow-up period for development of Alzheimer’s disease and all-cause dementia, 159 cases of dementia were identified, including 125 cases of Alzheimer’s disease. To evaluate which biomarkers may contribute to disease development, the researchers used sex-pooled and sex-specific Multivariable Cox Proportional Hazards models to control for other dementia risk factors such as age, education, APOE e4 allele status, plasma docosahexaenoic acid levels, weight change, and BMI.

Plasma insulin, glucose, and glycated albumin levels as well as the inflammatory marker lipoprotein-associated phospholipase A2 were not linked with Alzheimer’s disease or all-cause dementia. Although high-sensitivity C-reactive protein initially seemed to be associated with a lower risk of Alzheimer’s disease and dementia, adjustment for the APOE e4 allele and other factors revealed that the association was not significant. The investigators identified adiponectin as the only factor associated with a higher risk of all-cause dementia and Alzheimer’s disease in women.

Furthermore, women with baseline adiponectin levels greater than the sex-specific median showed a higher risk of all-cause dementia, compared to women with adiponectin values less than the median, even after adjustment for other risk factors.

“It is well established that insulin signaling is dysfunctional in the brains of patients with Alzheimer’s disease, and since adiponectin enhances insulin sensitivity, one would also expect beneficial actions protecting against cognitive decline,” Dr. van Himbergen’s group noted. “Our data, however, indicated that elevated adiponectin level was associated with an increased risk of dementia and Alzheimer’s disease in women.”
van Himbergen TM, Beiser AS, Ai M, et al. Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and Alzheimer disease. Arch Neurol. 2012 Jan 2; [Epub ahead of print].

Demographic and Clinical Factors Influence Survival of Patients With Parkinson’s Disease
Clinical conditions such as dementia and demographic factors such as race, sex, and age influence the survival rates of patients with Parkinson’s disease, according to research published in the January 2 issue of Archives of Neurology.

To determine the life expectancy of patients with Parkinson’s disease in the United States and identify factors that influence survival, Allison W. Willis, MD, of the Department of Neurology at the Washington University School of Medicine in St. Louis, and colleagues conducted a retrospective cohort study of 138,728 Medicare beneficiaries with incident Parkinson’s disease. Patients were 65 and older, and the population included 65,423 men and 73,305 women. The researchers identified the patients in 2002 and followed up through 2008.

The main outcome measures were confounder-adjusted six-year risk of death as influenced by three groups of factors, including race, sex, and age at diagnosis; geography and environmental factors; and clinical conditions. Dr. Willis examined hospitalization diagnoses in patients with terminal Parkinson’s disease and compared disease mortality with that of other common diseases.

Sixty-four percent of patients with Parkinson’s disease died during the six-year study, and the authors found that “sex and race significantly predicted survival.” Women with Parkinson’s disease had a 26% lower adjusted risk of death than men. African Americans and whites had the two highest crude death rates at 66.4% and 64.6%, respectively. Hispanics had a lower death rate (ie, 55.4%), and Asians had the lowest death rate (50.8%). Survival decreased with age.

Dementia was diagnosed in 69.6% of cases and was associated with a greater likelihood of death. Patients with Parkinson’s disease and dementia had a 28.1% survival rate, while patients without dementia had a 53.9% survival rate. Patients with dementia and Parkinson’s disease were 72% more likely to die during the study, and dementia had the strongest effect on age-adjusted survival among the variables studied, according to the authors.

Survival rates were similar across states, between regions of the country, and by rural or urban classification. However, patients with Parkinson’s disease who lived in urban areas and areas of high industrial metal emissions had a slightly higher adjusted risk of death (19%). Dr. Willis and her colleagues concluded that more research was needed to understand whether environmental exposures influence survival among patients with Parkinson’s disease.
Willis AW, Schootman M, Kung N, et al. Predictors of survival in patients with Parkinson disease. Arch Neurol. 2012 Jan 2; [Epub ahead of print].

Latent Epstein-Barr Virus May Activate Innate Immune Responses in the MS Brain
Latent Epstein-Barr virus (EBV) infection may contribute to neuroinflammation in patients with multiple sclerosis (MS), according to research published in the January 3 issue of Neurology.

A team led by J. S. Tzartos, DPhil, of the Department of Neuropathology, John Radcliffe Hospital, University of Oxford, United Kingdom, studied whether the activation of innate immune responses was associated with the presence of EBV in brains afflicted with MS. The group used immunohistochemistry to analyze 10 samples of white matter postmortem MS and 11 samples of control tissue for the expression of the proinflammatory cytokine interferon α (IFNα). The researchers also analyzed the samples for EBV using EBV-encoded RNA (EBER) in situ hybridization.

Dr. Tzartos and colleagues found overexpression of IFNα in active areas of white matter MS lesions, but not in inactive MS lesions, normal-appearing white matter, or normal brains. The team also found EBERs in areas where IFNα was overexpressed in active MS lesions. EBER+ cells were present in samples taken from CNS lymphoma and stroke cases, but not in other control brains. After transfecting EBERs into human embryonic kidney cells, the researchers found that the former elicited IFNα production in vitro.

“As we found EBER+ cells not only in white matter areas of these active MS lesions, but also CNS lymphoma and two cases of stroke, we conclude that the presence of EBV may not be unique to the MS brain, in contrast to previous findings,” wrote Dr. Tzartos. “Thus, our study casts new light on mechanistic interactions of viral RNAs and innate immune activation in the CNS, and may highlight the propensity of latent viral infections to contribute to neuroinflammation in the CNS, not only in MS, but also in other neuroinflammatory diseases.”

Dr. Tzartos’s findings “revitalize a debate that was heading toward a negative conclusion, that is, EBV-infected B cells are a rare and coincidental finding in MS brains,” wrote Jan D. Lünemann, MD, of the University of Zürich, in an accompanying editorial. An accumulation of EBV-infected B cells in inflammatory CNS lesions, which are rich in B cells, may represent a bystander phenomenon, but “bystanders do not necessarily remain silent and innocent,” wrote Dr. Lünemann.
Tzartos JS, Khan G, Vossenkamper A, et al. Association of innate immune activation with latent Epstein-Barr virus in active MS lesions. Neurology. 2012;78(1):15–23.
Lünemann JD, Epstein–Barr virus in multiple sclerosis. Neurology. 2012;78(1):11–12.

High Adiponectin Levels May Increase Dementia Risk in Women
Women with elevated plasma adiponectin levels may have an increased risk of developing both all-cause dementia and Alzheimer’s disease, researchers reported in the January 2 online issue of Archives of Neurology.

Thomas M. van Himbergen, PhD, a postdoctoral associate at the Lipid Metabolism Laboratory at Tufts University in Boston, and colleagues examined biomarkers for glucose homeostasis (ie, adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (ie, high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) in a prospective cohort study that included 840 dementia-free participants in the Framingham Heart Study. The participants, 541 of whom were women, had a median age of 76, and the researchers measured subjects’ sera for biomarkers at the 19th biennial examination (1985 to 1988).

During the mean 13-year follow-up period for development of Alzheimer’s disease and all-cause dementia, 159 cases of dementia were identified, including 125 cases of Alzheimer’s disease. To evaluate which biomarkers may contribute to disease development, the researchers used sex-pooled and sex-specific Multivariable Cox Proportional Hazards models to control for other dementia risk factors such as age, education, APOE e4 allele status, plasma docosahexaenoic acid levels, weight change, and BMI.

Plasma insulin, glucose, and glycated albumin levels as well as the inflammatory marker lipoprotein-associated phospholipase A2 were not linked with Alzheimer’s disease or all-cause dementia. Although high-sensitivity C-reactive protein initially seemed to be associated with a lower risk of Alzheimer’s disease and dementia, adjustment for the APOE e4 allele and other factors revealed that the association was not significant. The investigators identified adiponectin as the only factor associated with a higher risk of all-cause dementia and Alzheimer’s disease in women.

Furthermore, women with baseline adiponectin levels greater than the sex-specific median showed a higher risk of all-cause dementia, compared to women with adiponectin values less than the median, even after adjustment for other risk factors.

“It is well established that insulin signaling is dysfunctional in the brains of patients with Alzheimer’s disease, and since adiponectin enhances insulin sensitivity, one would also expect beneficial actions protecting against cognitive decline,” Dr. van Himbergen’s group noted. “Our data, however, indicated that elevated adiponectin level was associated with an increased risk of dementia and Alzheimer’s disease in women.”
van Himbergen TM, Beiser AS, Ai M, et al. Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and Alzheimer disease. Arch Neurol. 2012 Jan 2; [Epub ahead of print].

Researchers will prospectively assess clinical information, MRI data, blood biomarkers, and genetic variables to evaluate risk factors that affect MS disease progression.

AMSTERDAM—Researchers have established the Serial Unified Multicenter Multiple Sclerosis (MS) Investigation (SUMMIT) international consortium to prospectively evaluate risk factors that affect disease progression in a large, multinational cohort of patients with MS, according to a presentation at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in MS.

“Such longitudinal studies will be needed to understand disease progression in the modern era of treatment,” Howard L. Weiner, MD, Professor of Neurology at Harvard Medical School in Boston, and his colleagues noted.

Evaluating Disease Progression Factors
To predict factors affecting disease progression, Dr. Weiner’s team will assess clinical information, MRI data, blood biomarkers, and genetic variables from 1,500 patients with MS enrolled at international MS Centers in Boston; San Francisco; Basel, Switzerland; and Amsterdam. Each European site will contribute 250 patients to the SUMMIT study, while each US site will contribute 500 patients.

“We hope to present initial results at next year’s ECTRIMS, and we hope the SUMMIT will follow patients for at least a decade,” Dr. Weiner told Neurology Reviews.

Data collection for the study began in 2011, and the sites will maintain communication throughout the process with conference calls and bi-annual meetings.

Each year, the researchers will collect standardized clinical data on all patients, including medical and family history, the date and features of disease onset, relapse details, and current and historical treatments. The investigators will also analyze results obtained from the Symbol Digit Modalities Test, the Ambulation Index, and the Expanded Disability Status Scale (EDSS).

In addition, Dr. Weiner’s team developed a standardized questionnaire to obtain information about patient demographics, as well as epidemiologic factors such as alcohol and smoking history, diet and allergies, vitamin D intake, and vaccination history. To evaluate influences specific to females, the study will obtain data on menses onset, pregnancy, breast-feeding, fertility treatments, menopause, and hormone medications. 

Biologic samples from all participants will be collected to assess antigen microarrays, RNA microarrays, vitamin D levels, and serum biomarkers, and MRI will be used to measure T2 lesion volume, normalized brain volume, and gadolinium-enhancing lesions. The researchers added that, “A genome-wide meta-analysis for single nucleotide polymorphisms that influence clinical and MRI outcome measures is planned.”

Current Progress and Future Outcomes
Thus far, the SUMMIT study has made some progress toward its goals. The team obtained institutional review board (human studies) approval, established a data collection platform and uniform collection forms and fields, and created working groups.

The research group anticipates using statistical methodologies and computerized analysis software to analyze univariate and multivariate predictors of disease progression. “We think that MRI, biomarkers, and clinical features of the patients will be the most influential,” Dr. Weiner commented.

The investigators expect to add more collaborative partners to the study in the future. Dr. Weiner explained, “Once the SUMMIT structure has been firmly established and is operational, which should take approximately one more year, we will be talking to other MS centers to see if any are interested in participating and how to provide for long-term funding.

“We hope the clinical implications will relate to understanding the course of disease in individual patients and how to modify factors that will affect long-term progression,” he concluded.                                 

Researchers will prospectively assess clinical information, MRI data, blood biomarkers, and genetic variables to evaluate risk factors that affect MS disease progression.

AMSTERDAM—Researchers have established the Serial Unified Multicenter Multiple Sclerosis (MS) Investigation (SUMMIT) international consortium to prospectively evaluate risk factors that affect disease progression in a large, multinational cohort of patients with MS, according to a presentation at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in MS.

“Such longitudinal studies will be needed to understand disease progression in the modern era of treatment,” Howard L. Weiner, MD, Professor of Neurology at Harvard Medical School in Boston, and his colleagues noted.

Evaluating Disease Progression Factors
To predict factors affecting disease progression, Dr. Weiner’s team will assess clinical information, MRI data, blood biomarkers, and genetic variables from 1,500 patients with MS enrolled at international MS Centers in Boston; San Francisco; Basel, Switzerland; and Amsterdam. Each European site will contribute 250 patients to the SUMMIT study, while each US site will contribute 500 patients.

“We hope to present initial results at next year’s ECTRIMS, and we hope the SUMMIT will follow patients for at least a decade,” Dr. Weiner told Neurology Reviews.

Data collection for the study began in 2011, and the sites will maintain communication throughout the process with conference calls and bi-annual meetings.

Each year, the researchers will collect standardized clinical data on all patients, including medical and family history, the date and features of disease onset, relapse details, and current and historical treatments. The investigators will also analyze results obtained from the Symbol Digit Modalities Test, the Ambulation Index, and the Expanded Disability Status Scale (EDSS).

In addition, Dr. Weiner’s team developed a standardized questionnaire to obtain information about patient demographics, as well as epidemiologic factors such as alcohol and smoking history, diet and allergies, vitamin D intake, and vaccination history. To evaluate influences specific to females, the study will obtain data on menses onset, pregnancy, breast-feeding, fertility treatments, menopause, and hormone medications. 

Biologic samples from all participants will be collected to assess antigen microarrays, RNA microarrays, vitamin D levels, and serum biomarkers, and MRI will be used to measure T2 lesion volume, normalized brain volume, and gadolinium-enhancing lesions. The researchers added that, “A genome-wide meta-analysis for single nucleotide polymorphisms that influence clinical and MRI outcome measures is planned.”

Current Progress and Future Outcomes
Thus far, the SUMMIT study has made some progress toward its goals. The team obtained institutional review board (human studies) approval, established a data collection platform and uniform collection forms and fields, and created working groups.

The research group anticipates using statistical methodologies and computerized analysis software to analyze univariate and multivariate predictors of disease progression. “We think that MRI, biomarkers, and clinical features of the patients will be the most influential,” Dr. Weiner commented.

The investigators expect to add more collaborative partners to the study in the future. Dr. Weiner explained, “Once the SUMMIT structure has been firmly established and is operational, which should take approximately one more year, we will be talking to other MS centers to see if any are interested in participating and how to provide for long-term funding.

“We hope the clinical implications will relate to understanding the course of disease in individual patients and how to modify factors that will affect long-term progression,” he concluded.                                 

Researchers will prospectively assess clinical information, MRI data, blood biomarkers, and genetic variables to evaluate risk factors that affect MS disease progression.

AMSTERDAM—Researchers have established the Serial Unified Multicenter Multiple Sclerosis (MS) Investigation (SUMMIT) international consortium to prospectively evaluate risk factors that affect disease progression in a large, multinational cohort of patients with MS, according to a presentation at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in MS.

“Such longitudinal studies will be needed to understand disease progression in the modern era of treatment,” Howard L. Weiner, MD, Professor of Neurology at Harvard Medical School in Boston, and his colleagues noted.

Evaluating Disease Progression Factors
To predict factors affecting disease progression, Dr. Weiner’s team will assess clinical information, MRI data, blood biomarkers, and genetic variables from 1,500 patients with MS enrolled at international MS Centers in Boston; San Francisco; Basel, Switzerland; and Amsterdam. Each European site will contribute 250 patients to the SUMMIT study, while each US site will contribute 500 patients.

“We hope to present initial results at next year’s ECTRIMS, and we hope the SUMMIT will follow patients for at least a decade,” Dr. Weiner told Neurology Reviews.

Data collection for the study began in 2011, and the sites will maintain communication throughout the process with conference calls and bi-annual meetings.

Each year, the researchers will collect standardized clinical data on all patients, including medical and family history, the date and features of disease onset, relapse details, and current and historical treatments. The investigators will also analyze results obtained from the Symbol Digit Modalities Test, the Ambulation Index, and the Expanded Disability Status Scale (EDSS).

In addition, Dr. Weiner’s team developed a standardized questionnaire to obtain information about patient demographics, as well as epidemiologic factors such as alcohol and smoking history, diet and allergies, vitamin D intake, and vaccination history. To evaluate influences specific to females, the study will obtain data on menses onset, pregnancy, breast-feeding, fertility treatments, menopause, and hormone medications. 

Biologic samples from all participants will be collected to assess antigen microarrays, RNA microarrays, vitamin D levels, and serum biomarkers, and MRI will be used to measure T2 lesion volume, normalized brain volume, and gadolinium-enhancing lesions. The researchers added that, “A genome-wide meta-analysis for single nucleotide polymorphisms that influence clinical and MRI outcome measures is planned.”

Current Progress and Future Outcomes
Thus far, the SUMMIT study has made some progress toward its goals. The team obtained institutional review board (human studies) approval, established a data collection platform and uniform collection forms and fields, and created working groups.

The research group anticipates using statistical methodologies and computerized analysis software to analyze univariate and multivariate predictors of disease progression. “We think that MRI, biomarkers, and clinical features of the patients will be the most influential,” Dr. Weiner commented.

The investigators expect to add more collaborative partners to the study in the future. Dr. Weiner explained, “Once the SUMMIT structure has been firmly established and is operational, which should take approximately one more year, we will be talking to other MS centers to see if any are interested in participating and how to provide for long-term funding.

“We hope the clinical implications will relate to understanding the course of disease in individual patients and how to modify factors that will affect long-term progression,” he concluded.                                 

Researchers conduct a retrospective study to determine whether children with MS can be diagnosed after an initial event and MRI.

SAVANNAH, GA—Applying the 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis (MS) could have led to an earlier diagnosis among some pediatric demyelinating patients, according to research presented at the 40th National Meeting of the Child Neurology Society.

“Revised 2010 MS diagnostic criteria now allow a single brain MRI with more than one T2 lesion in at least two regions and one enhancing lesion to fulfill dissemination in time and space,” noted Thitiwan Simasathien, MD, Child Neurology Fellow, and Jayne M. Ness, MD, PhD, Associate Professor, both at the University of Alabama in Birmingham. “However, this streamlined diagnosis of MS had not been validated in pediatric demyelinating patients.”

Evaluating the 2010 MS Diagnostic Criteria
The investigators conducted a retrospective chart review evaluating the utility of the 2010 MS diagnostic criteria in a cohort of 42 pediatric patients with MS. All participants (70% female, 40% African American) were younger than 18 and presented with clinically isolated syndrome (CIS) from 1998 to 2008, with a mean onset age of 13.1. Of the patients, none were documented with encephalopathy, six presented with optic neuritis (five unilateral, one bilateral), and 36 presented with pyramidal or brainstem symptoms.

The researchers determined whether the first MRI conducted on these patients fulfilled 2010 MS diagnostic criteria, finding that 40% of the cohort (17/42) showed dissemination in time and space on their initial MRI. Drs. Simasathien and Ness noted no differences in age, race, or sex between patients who met the 2010 diagnostic criteria and those who did not.

If the 2010 criteria had been applied to the participants at the time of their initial CIS presentation, some patients could have received an earlier diagnosis of MS and potentially could have begun disease-modifying therapy sooner, the investigators concluded. Although the findings of the retrospective study show promise, “Further study is necessary to assess the validity of these criteria in pediatric demyelinating patients,” the researchers stated.

Dr. Ness told Neurology Reviews, “It will be critical to assess whether the streamlined 2010 McDonald criteria have appropriate specificity to ensure that children with self-limited demyelinating syndromes—such as acute disseminated encephalomyelitis or conditions requiring different treatment approaches, such as neuromyelitis optica—are not incorrectly diagnosed with MS.”                     

Researchers conduct a retrospective study to determine whether children with MS can be diagnosed after an initial event and MRI.

SAVANNAH, GA—Applying the 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis (MS) could have led to an earlier diagnosis among some pediatric demyelinating patients, according to research presented at the 40th National Meeting of the Child Neurology Society.

“Revised 2010 MS diagnostic criteria now allow a single brain MRI with more than one T2 lesion in at least two regions and one enhancing lesion to fulfill dissemination in time and space,” noted Thitiwan Simasathien, MD, Child Neurology Fellow, and Jayne M. Ness, MD, PhD, Associate Professor, both at the University of Alabama in Birmingham. “However, this streamlined diagnosis of MS had not been validated in pediatric demyelinating patients.”

Evaluating the 2010 MS Diagnostic Criteria
The investigators conducted a retrospective chart review evaluating the utility of the 2010 MS diagnostic criteria in a cohort of 42 pediatric patients with MS. All participants (70% female, 40% African American) were younger than 18 and presented with clinically isolated syndrome (CIS) from 1998 to 2008, with a mean onset age of 13.1. Of the patients, none were documented with encephalopathy, six presented with optic neuritis (five unilateral, one bilateral), and 36 presented with pyramidal or brainstem symptoms.

The researchers determined whether the first MRI conducted on these patients fulfilled 2010 MS diagnostic criteria, finding that 40% of the cohort (17/42) showed dissemination in time and space on their initial MRI. Drs. Simasathien and Ness noted no differences in age, race, or sex between patients who met the 2010 diagnostic criteria and those who did not.

If the 2010 criteria had been applied to the participants at the time of their initial CIS presentation, some patients could have received an earlier diagnosis of MS and potentially could have begun disease-modifying therapy sooner, the investigators concluded. Although the findings of the retrospective study show promise, “Further study is necessary to assess the validity of these criteria in pediatric demyelinating patients,” the researchers stated.

Dr. Ness told Neurology Reviews, “It will be critical to assess whether the streamlined 2010 McDonald criteria have appropriate specificity to ensure that children with self-limited demyelinating syndromes—such as acute disseminated encephalomyelitis or conditions requiring different treatment approaches, such as neuromyelitis optica—are not incorrectly diagnosed with MS.”                     

Researchers conduct a retrospective study to determine whether children with MS can be diagnosed after an initial event and MRI.

SAVANNAH, GA—Applying the 2010 Revised McDonald Diagnostic Criteria for Multiple Sclerosis (MS) could have led to an earlier diagnosis among some pediatric demyelinating patients, according to research presented at the 40th National Meeting of the Child Neurology Society.

“Revised 2010 MS diagnostic criteria now allow a single brain MRI with more than one T2 lesion in at least two regions and one enhancing lesion to fulfill dissemination in time and space,” noted Thitiwan Simasathien, MD, Child Neurology Fellow, and Jayne M. Ness, MD, PhD, Associate Professor, both at the University of Alabama in Birmingham. “However, this streamlined diagnosis of MS had not been validated in pediatric demyelinating patients.”

Evaluating the 2010 MS Diagnostic Criteria
The investigators conducted a retrospective chart review evaluating the utility of the 2010 MS diagnostic criteria in a cohort of 42 pediatric patients with MS. All participants (70% female, 40% African American) were younger than 18 and presented with clinically isolated syndrome (CIS) from 1998 to 2008, with a mean onset age of 13.1. Of the patients, none were documented with encephalopathy, six presented with optic neuritis (five unilateral, one bilateral), and 36 presented with pyramidal or brainstem symptoms.

The researchers determined whether the first MRI conducted on these patients fulfilled 2010 MS diagnostic criteria, finding that 40% of the cohort (17/42) showed dissemination in time and space on their initial MRI. Drs. Simasathien and Ness noted no differences in age, race, or sex between patients who met the 2010 diagnostic criteria and those who did not.

If the 2010 criteria had been applied to the participants at the time of their initial CIS presentation, some patients could have received an earlier diagnosis of MS and potentially could have begun disease-modifying therapy sooner, the investigators concluded. Although the findings of the retrospective study show promise, “Further study is necessary to assess the validity of these criteria in pediatric demyelinating patients,” the researchers stated.

Dr. Ness told Neurology Reviews, “It will be critical to assess whether the streamlined 2010 McDonald criteria have appropriate specificity to ensure that children with self-limited demyelinating syndromes—such as acute disseminated encephalomyelitis or conditions requiring different treatment approaches, such as neuromyelitis optica—are not incorrectly diagnosed with MS.”                     

Two surveys of American multiple sclerosis (MS) specialists reveal a general consensus of practice patterns in primary and secondary progressive MS, relapsing-remitting MS, and clinically isolated syndrome.

AMSTERDAM—Neurologists from multiple sclerosis (MS) treatment centers across the US generally agree on the use of spinal MRI or lumbar puncture for diagnosis of the disease, but more research regarding treatment responses and therapies is needed, according to the results of two studies presented at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

“The current research effort was conducted with the goal of gaining an understanding of the current diagnostic and treatment practices of MS specialists at US MS treatment centers,” the investigators stated. The surveys were designed to determine the influence and use of various diagnostic and clinical parameters in clinical decisions pertaining to disease-modifying therapy initiation, switching, and selection.

The team of researchers, led by Omar A. Khan, MD, from the Department of Neurology at Wayne State University in Detroit, and Carlo Tornatore, MD, from the Department of Neurology at Georgetown University in Washington, DC, invited neurologists from 207 MS treatment centers to participate in the study. Two web-based surveys evaluating practice patterns for various forms of MS were developed and distributed to specialists; 75 specialists completed the first survey, and 71 of those completed the second survey.

CIS, RIS, and RRMS
The investigators presented participating MS specialists with patient scenarios regarding clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and radiologically isolated syndrome (RIS). Regarding CIS, the MS specialists reached a clear consensus (more than 75%)—MRI lesions are considered predictive of disease activity and a follow-up MRI within three to six months is important to confirm treatment effect. Optic neuritis alone was viewed as insufficient for initiating therapy. Glatiramer acetate and interferon beta were the most common initial therapy choices for CIS.

When treating RRMS with mild symptoms, most respondents also chose interferon beta and glatiramer acetate as their preferred initial therapy choices. “Treatment-naive patients with RRMS are generally started on a disease-modifying therapy,” the researchers concluded. “Disease-modifying therapies are generally switched with three or more new lesions on brain MRI over 12 months.”

The survey respondents also reached a consensus that MRI change over 12 months is a criterion for switching therapies in patients with RRMS and breakthrough disease, despite treatment with a first-line disease-modifying therapy. When interferon beta was used to treat these patients, there was a general trend toward using natalizumab as the disease progressed. For RIS, survey respondents agreed that “a spinal cord MRI is generally performed as part of the diagnostic evaluation,” and that lumbar puncture does not seem to have a major diagnostic role.

“For RRMS, the data suggested that with growing clinical experience and an increasing variety of therapeutic options, physicians may feel more confident in the use of more complex agents and treatment regimens,” the investigators stated. “The finding that nearly all respondents would perform a follow-up MRI for RIS reflects physician recognition that some patients with RIS will develop clinically definite MS and suggests that this cohort should be monitored for MRI lesion progression or evidence of clinical MS disease activity."

Two surveys of American multiple sclerosis (MS) specialists reveal a general consensus of practice patterns in primary and secondary progressive MS, relapsing-remitting MS, and clinically isolated syndrome.

AMSTERDAM—Neurologists from multiple sclerosis (MS) treatment centers across the US generally agree on the use of spinal MRI or lumbar puncture for diagnosis of the disease, but more research regarding treatment responses and therapies is needed, according to the results of two studies presented at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

“The current research effort was conducted with the goal of gaining an understanding of the current diagnostic and treatment practices of MS specialists at US MS treatment centers,” the investigators stated. The surveys were designed to determine the influence and use of various diagnostic and clinical parameters in clinical decisions pertaining to disease-modifying therapy initiation, switching, and selection.

The team of researchers, led by Omar A. Khan, MD, from the Department of Neurology at Wayne State University in Detroit, and Carlo Tornatore, MD, from the Department of Neurology at Georgetown University in Washington, DC, invited neurologists from 207 MS treatment centers to participate in the study. Two web-based surveys evaluating practice patterns for various forms of MS were developed and distributed to specialists; 75 specialists completed the first survey, and 71 of those completed the second survey.

CIS, RIS, and RRMS
The investigators presented participating MS specialists with patient scenarios regarding clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and radiologically isolated syndrome (RIS). Regarding CIS, the MS specialists reached a clear consensus (more than 75%)—MRI lesions are considered predictive of disease activity and a follow-up MRI within three to six months is important to confirm treatment effect. Optic neuritis alone was viewed as insufficient for initiating therapy. Glatiramer acetate and interferon beta were the most common initial therapy choices for CIS.

When treating RRMS with mild symptoms, most respondents also chose interferon beta and glatiramer acetate as their preferred initial therapy choices. “Treatment-naive patients with RRMS are generally started on a disease-modifying therapy,” the researchers concluded. “Disease-modifying therapies are generally switched with three or more new lesions on brain MRI over 12 months.”

The survey respondents also reached a consensus that MRI change over 12 months is a criterion for switching therapies in patients with RRMS and breakthrough disease, despite treatment with a first-line disease-modifying therapy. When interferon beta was used to treat these patients, there was a general trend toward using natalizumab as the disease progressed. For RIS, survey respondents agreed that “a spinal cord MRI is generally performed as part of the diagnostic evaluation,” and that lumbar puncture does not seem to have a major diagnostic role.

“For RRMS, the data suggested that with growing clinical experience and an increasing variety of therapeutic options, physicians may feel more confident in the use of more complex agents and treatment regimens,” the investigators stated. “The finding that nearly all respondents would perform a follow-up MRI for RIS reflects physician recognition that some patients with RIS will develop clinically definite MS and suggests that this cohort should be monitored for MRI lesion progression or evidence of clinical MS disease activity."

Two surveys of American multiple sclerosis (MS) specialists reveal a general consensus of practice patterns in primary and secondary progressive MS, relapsing-remitting MS, and clinically isolated syndrome.

AMSTERDAM—Neurologists from multiple sclerosis (MS) treatment centers across the US generally agree on the use of spinal MRI or lumbar puncture for diagnosis of the disease, but more research regarding treatment responses and therapies is needed, according to the results of two studies presented at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

“The current research effort was conducted with the goal of gaining an understanding of the current diagnostic and treatment practices of MS specialists at US MS treatment centers,” the investigators stated. The surveys were designed to determine the influence and use of various diagnostic and clinical parameters in clinical decisions pertaining to disease-modifying therapy initiation, switching, and selection.

The team of researchers, led by Omar A. Khan, MD, from the Department of Neurology at Wayne State University in Detroit, and Carlo Tornatore, MD, from the Department of Neurology at Georgetown University in Washington, DC, invited neurologists from 207 MS treatment centers to participate in the study. Two web-based surveys evaluating practice patterns for various forms of MS were developed and distributed to specialists; 75 specialists completed the first survey, and 71 of those completed the second survey.

CIS, RIS, and RRMS
The investigators presented participating MS specialists with patient scenarios regarding clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), and radiologically isolated syndrome (RIS). Regarding CIS, the MS specialists reached a clear consensus (more than 75%)—MRI lesions are considered predictive of disease activity and a follow-up MRI within three to six months is important to confirm treatment effect. Optic neuritis alone was viewed as insufficient for initiating therapy. Glatiramer acetate and interferon beta were the most common initial therapy choices for CIS.

When treating RRMS with mild symptoms, most respondents also chose interferon beta and glatiramer acetate as their preferred initial therapy choices. “Treatment-naive patients with RRMS are generally started on a disease-modifying therapy,” the researchers concluded. “Disease-modifying therapies are generally switched with three or more new lesions on brain MRI over 12 months.”

The survey respondents also reached a consensus that MRI change over 12 months is a criterion for switching therapies in patients with RRMS and breakthrough disease, despite treatment with a first-line disease-modifying therapy. When interferon beta was used to treat these patients, there was a general trend toward using natalizumab as the disease progressed. For RIS, survey respondents agreed that “a spinal cord MRI is generally performed as part of the diagnostic evaluation,” and that lumbar puncture does not seem to have a major diagnostic role.

“For RRMS, the data suggested that with growing clinical experience and an increasing variety of therapeutic options, physicians may feel more confident in the use of more complex agents and treatment regimens,” the investigators stated. “The finding that nearly all respondents would perform a follow-up MRI for RIS reflects physician recognition that some patients with RIS will develop clinically definite MS and suggests that this cohort should be monitored for MRI lesion progression or evidence of clinical MS disease activity."

AMSTERDAM—R­ecent clinical trials for several multiple sclerosis (MS) treatments have yielded promising results and insights into the disease pathogenesis and have provided direction for future research and diagnostic criteria, Ludwig Kappos, MD, reported at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Prof. Kappos, Professor in the Departments of Neurology and Biomedicine, University of Basel, Switzerland, reviewed the safety and efficacy profiles of fingolimod, natalizumab, teriflunomide, and other potential therapies for MS in development, while highlighting the advancements that have been achieved through clinical trials.

Clinical trials helped to introduce more and more effective compounds and treatment algorithms for the management of relapsing MS and clinically isolated syndromes,” Prof. Kappos said. “Clinical results and effects stimulate new directions, be they diagnostic observations or therapeutic successes…. [They] have played an ever-increasing role in shaping our armamentarium against this still enigmatic disease.”

Improvements in Pathogenesis Understanding
According to Prof. Kappos, one of the main achievements of developing new therapies for MS is the increased insight into disease pathogenesis. “We have detected or found out about the effects of compounds whose modes of action we initially misunderstood,” he said. “Through exploring this mode of action, we are also learning much about the pathogenesis of MS.”

Recent research has validated the role of the immune system in disease pathogenesis and also opened new pathways for developing drugs that address the blood-brain barrier, T and B cells, regulatory cells, and cytokines. “Based on currently completed or ongoing studies, a large number of new compounds, especially oral immunomodulators and monoclonal antibodies, are waiting to enter our pharmacology within the next two to four years,” Prof. Kappos said.

Monoclonal Antibodies
Natalizumab, a humanized monoclonal antibody, has proven effective in reducing relapse rates in MS, but it also has been linked to an increased risk for progressive multifocal leukoencephalopathy (PML), Prof. Kappos noted. The drug does not seem to have any additional immunosuppressive effect, and “it is difficult to understand the selectivity of this risk for PML that is created by this compound,” he said. “Other risks have not really occurred, so it must be something specific that we have to explore in more detail.”

Prof. Kappos also discussed rituximab and ocrelizumab, two anti-CD20 monoclonal antibodies that exert their neuroprotective effect through B cell depletion. Rituximab, when compared with interferon-beta, was shown to significantly reduce relapse rates, and was well tolerated, with approximately 90% of study participants remaining in the study for two years. “At the end of this two-year period, all but two patients on this treatment did not have any active new lesions and were free of disease activity as dictated by the MRI scan,” he reported. In a phase II, placebo-controlled study, ocrelizumab was shown to reduce the number of gadolinium-enhancing lesions in patients with relapsing-remitting MS.

Oral Immunomodulators
Fingolimod, an immunomodulator that has achieved “very encouraging results” in phase III studies, “expands on the lessons we learned in the development of ocrelizumab,” Prof. Kappos explained. “One unexpected finding that emerged out of the phase III studies … was a 30% reduction of atrophy or loss of brain volume,” he added. “Fortunately, although it has so many possible interactions in the body, the comprehensive safety program did not yield real issues of concern over the first course [of treatment]. There remain a few questions about long-term safety and efficacy and better understanding of the mode of action, and the profile of the responders.”

Another immunomodulatory compound that has completed phase III studies is teriflunomide, a metabolite of leflunomide. “It’s a more conservative approach to treatment, as it is an immunomodulator with some more selective effects,” Prof. Kappos said. “The effects were less pronounced if you look at the increase in relapse rates … and less pronounced, but dose-dependently increased, regarding T2 and gadolinium MRI criteria.” He reported that the adverse event profile for teriflunomide was “quite reassuring.”

“Laquinimod, another compound that has now finished two studies, is an immunomodulator whose mode of action we have just started to understand,” Prof. Kappos stated. “What is very clear, both in experimental animal and human trials, is that it didn’t exert any immunosuppressive effect.” Patients on this treatment did not experience an increase in infections, and there was evidence that laquinimod exerted some neuroprotective properties by reducing brain atrophy.

Prof. Kappos also discussed the compound dimethyl fumarate as a therapeutic agent for MS, whose mechanism of action is related to its anti-inflammatory effect. “It may be the first drug that acts both on psoriasis and MS,” he noted. “However, it also may interact with pathways that protect the CNS.” Clinical trials showed a reduction in the annualized relapse rate and disability progression, “but there was an impact on the quality of life,” Prof. Kappos noted.

Current Challenges and Future Directions
“At the moment, we are faced with different treatment options that will probably be in daily practice within the next two to four years,” Prof. Kappos stated. “Much of the evidence is not yet published or peer reviewed, but still there are some indications that may help us to define a profile of these compounds…. [Through clinical trials] we learned about the importance of early intervention and—mainly through negative studies—that later MS stages and progressive disease courses respond in a different way to treatments and need different study designs and more advanced outcome measures.”   

Many achievements have been made as a result of successful clinical trials in MS therapy, including new treatment algorithms and diagnostic MRI criteria, but several challenges remain, according to Prof. Kappos. “We have to adapt and further develop our concepts, we have to develop criteria for phase- and cause-adaptive differential indications, and we have to further explore benefits and risks of new compounds … with additional phase III-B and IV studies…. Future research will focus on the interactions of microglia and their role in the development of disability and deficits in MS.

“Investigator-initiated and publicly funded prospective and comprehensive observational and cohort studies must increasingly complement the current paradigm of mostly corporate-sponsored clinical trials,” Prof. Kappos concluded.  

—Ariel Jones  

AMSTERDAM—R­ecent clinical trials for several multiple sclerosis (MS) treatments have yielded promising results and insights into the disease pathogenesis and have provided direction for future research and diagnostic criteria, Ludwig Kappos, MD, reported at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Prof. Kappos, Professor in the Departments of Neurology and Biomedicine, University of Basel, Switzerland, reviewed the safety and efficacy profiles of fingolimod, natalizumab, teriflunomide, and other potential therapies for MS in development, while highlighting the advancements that have been achieved through clinical trials.

Clinical trials helped to introduce more and more effective compounds and treatment algorithms for the management of relapsing MS and clinically isolated syndromes,” Prof. Kappos said. “Clinical results and effects stimulate new directions, be they diagnostic observations or therapeutic successes…. [They] have played an ever-increasing role in shaping our armamentarium against this still enigmatic disease.”

Improvements in Pathogenesis Understanding
According to Prof. Kappos, one of the main achievements of developing new therapies for MS is the increased insight into disease pathogenesis. “We have detected or found out about the effects of compounds whose modes of action we initially misunderstood,” he said. “Through exploring this mode of action, we are also learning much about the pathogenesis of MS.”

Recent research has validated the role of the immune system in disease pathogenesis and also opened new pathways for developing drugs that address the blood-brain barrier, T and B cells, regulatory cells, and cytokines. “Based on currently completed or ongoing studies, a large number of new compounds, especially oral immunomodulators and monoclonal antibodies, are waiting to enter our pharmacology within the next two to four years,” Prof. Kappos said.

Monoclonal Antibodies
Natalizumab, a humanized monoclonal antibody, has proven effective in reducing relapse rates in MS, but it also has been linked to an increased risk for progressive multifocal leukoencephalopathy (PML), Prof. Kappos noted. The drug does not seem to have any additional immunosuppressive effect, and “it is difficult to understand the selectivity of this risk for PML that is created by this compound,” he said. “Other risks have not really occurred, so it must be something specific that we have to explore in more detail.”

Prof. Kappos also discussed rituximab and ocrelizumab, two anti-CD20 monoclonal antibodies that exert their neuroprotective effect through B cell depletion. Rituximab, when compared with interferon-beta, was shown to significantly reduce relapse rates, and was well tolerated, with approximately 90% of study participants remaining in the study for two years. “At the end of this two-year period, all but two patients on this treatment did not have any active new lesions and were free of disease activity as dictated by the MRI scan,” he reported. In a phase II, placebo-controlled study, ocrelizumab was shown to reduce the number of gadolinium-enhancing lesions in patients with relapsing-remitting MS.

Oral Immunomodulators
Fingolimod, an immunomodulator that has achieved “very encouraging results” in phase III studies, “expands on the lessons we learned in the development of ocrelizumab,” Prof. Kappos explained. “One unexpected finding that emerged out of the phase III studies … was a 30% reduction of atrophy or loss of brain volume,” he added. “Fortunately, although it has so many possible interactions in the body, the comprehensive safety program did not yield real issues of concern over the first course [of treatment]. There remain a few questions about long-term safety and efficacy and better understanding of the mode of action, and the profile of the responders.”

Another immunomodulatory compound that has completed phase III studies is teriflunomide, a metabolite of leflunomide. “It’s a more conservative approach to treatment, as it is an immunomodulator with some more selective effects,” Prof. Kappos said. “The effects were less pronounced if you look at the increase in relapse rates … and less pronounced, but dose-dependently increased, regarding T2 and gadolinium MRI criteria.” He reported that the adverse event profile for teriflunomide was “quite reassuring.”

“Laquinimod, another compound that has now finished two studies, is an immunomodulator whose mode of action we have just started to understand,” Prof. Kappos stated. “What is very clear, both in experimental animal and human trials, is that it didn’t exert any immunosuppressive effect.” Patients on this treatment did not experience an increase in infections, and there was evidence that laquinimod exerted some neuroprotective properties by reducing brain atrophy.

Prof. Kappos also discussed the compound dimethyl fumarate as a therapeutic agent for MS, whose mechanism of action is related to its anti-inflammatory effect. “It may be the first drug that acts both on psoriasis and MS,” he noted. “However, it also may interact with pathways that protect the CNS.” Clinical trials showed a reduction in the annualized relapse rate and disability progression, “but there was an impact on the quality of life,” Prof. Kappos noted.

Current Challenges and Future Directions
“At the moment, we are faced with different treatment options that will probably be in daily practice within the next two to four years,” Prof. Kappos stated. “Much of the evidence is not yet published or peer reviewed, but still there are some indications that may help us to define a profile of these compounds…. [Through clinical trials] we learned about the importance of early intervention and—mainly through negative studies—that later MS stages and progressive disease courses respond in a different way to treatments and need different study designs and more advanced outcome measures.”   

Many achievements have been made as a result of successful clinical trials in MS therapy, including new treatment algorithms and diagnostic MRI criteria, but several challenges remain, according to Prof. Kappos. “We have to adapt and further develop our concepts, we have to develop criteria for phase- and cause-adaptive differential indications, and we have to further explore benefits and risks of new compounds … with additional phase III-B and IV studies…. Future research will focus on the interactions of microglia and their role in the development of disability and deficits in MS.

“Investigator-initiated and publicly funded prospective and comprehensive observational and cohort studies must increasingly complement the current paradigm of mostly corporate-sponsored clinical trials,” Prof. Kappos concluded.  

—Ariel Jones  

AMSTERDAM—R­ecent clinical trials for several multiple sclerosis (MS) treatments have yielded promising results and insights into the disease pathogenesis and have provided direction for future research and diagnostic criteria, Ludwig Kappos, MD, reported at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Prof. Kappos, Professor in the Departments of Neurology and Biomedicine, University of Basel, Switzerland, reviewed the safety and efficacy profiles of fingolimod, natalizumab, teriflunomide, and other potential therapies for MS in development, while highlighting the advancements that have been achieved through clinical trials.

Clinical trials helped to introduce more and more effective compounds and treatment algorithms for the management of relapsing MS and clinically isolated syndromes,” Prof. Kappos said. “Clinical results and effects stimulate new directions, be they diagnostic observations or therapeutic successes…. [They] have played an ever-increasing role in shaping our armamentarium against this still enigmatic disease.”

Improvements in Pathogenesis Understanding
According to Prof. Kappos, one of the main achievements of developing new therapies for MS is the increased insight into disease pathogenesis. “We have detected or found out about the effects of compounds whose modes of action we initially misunderstood,” he said. “Through exploring this mode of action, we are also learning much about the pathogenesis of MS.”

Recent research has validated the role of the immune system in disease pathogenesis and also opened new pathways for developing drugs that address the blood-brain barrier, T and B cells, regulatory cells, and cytokines. “Based on currently completed or ongoing studies, a large number of new compounds, especially oral immunomodulators and monoclonal antibodies, are waiting to enter our pharmacology within the next two to four years,” Prof. Kappos said.

Monoclonal Antibodies
Natalizumab, a humanized monoclonal antibody, has proven effective in reducing relapse rates in MS, but it also has been linked to an increased risk for progressive multifocal leukoencephalopathy (PML), Prof. Kappos noted. The drug does not seem to have any additional immunosuppressive effect, and “it is difficult to understand the selectivity of this risk for PML that is created by this compound,” he said. “Other risks have not really occurred, so it must be something specific that we have to explore in more detail.”

Prof. Kappos also discussed rituximab and ocrelizumab, two anti-CD20 monoclonal antibodies that exert their neuroprotective effect through B cell depletion. Rituximab, when compared with interferon-beta, was shown to significantly reduce relapse rates, and was well tolerated, with approximately 90% of study participants remaining in the study for two years. “At the end of this two-year period, all but two patients on this treatment did not have any active new lesions and were free of disease activity as dictated by the MRI scan,” he reported. In a phase II, placebo-controlled study, ocrelizumab was shown to reduce the number of gadolinium-enhancing lesions in patients with relapsing-remitting MS.

Oral Immunomodulators
Fingolimod, an immunomodulator that has achieved “very encouraging results” in phase III studies, “expands on the lessons we learned in the development of ocrelizumab,” Prof. Kappos explained. “One unexpected finding that emerged out of the phase III studies … was a 30% reduction of atrophy or loss of brain volume,” he added. “Fortunately, although it has so many possible interactions in the body, the comprehensive safety program did not yield real issues of concern over the first course [of treatment]. There remain a few questions about long-term safety and efficacy and better understanding of the mode of action, and the profile of the responders.”

Another immunomodulatory compound that has completed phase III studies is teriflunomide, a metabolite of leflunomide. “It’s a more conservative approach to treatment, as it is an immunomodulator with some more selective effects,” Prof. Kappos said. “The effects were less pronounced if you look at the increase in relapse rates … and less pronounced, but dose-dependently increased, regarding T2 and gadolinium MRI criteria.” He reported that the adverse event profile for teriflunomide was “quite reassuring.”

“Laquinimod, another compound that has now finished two studies, is an immunomodulator whose mode of action we have just started to understand,” Prof. Kappos stated. “What is very clear, both in experimental animal and human trials, is that it didn’t exert any immunosuppressive effect.” Patients on this treatment did not experience an increase in infections, and there was evidence that laquinimod exerted some neuroprotective properties by reducing brain atrophy.

Prof. Kappos also discussed the compound dimethyl fumarate as a therapeutic agent for MS, whose mechanism of action is related to its anti-inflammatory effect. “It may be the first drug that acts both on psoriasis and MS,” he noted. “However, it also may interact with pathways that protect the CNS.” Clinical trials showed a reduction in the annualized relapse rate and disability progression, “but there was an impact on the quality of life,” Prof. Kappos noted.

Current Challenges and Future Directions
“At the moment, we are faced with different treatment options that will probably be in daily practice within the next two to four years,” Prof. Kappos stated. “Much of the evidence is not yet published or peer reviewed, but still there are some indications that may help us to define a profile of these compounds…. [Through clinical trials] we learned about the importance of early intervention and—mainly through negative studies—that later MS stages and progressive disease courses respond in a different way to treatments and need different study designs and more advanced outcome measures.”   

Many achievements have been made as a result of successful clinical trials in MS therapy, including new treatment algorithms and diagnostic MRI criteria, but several challenges remain, according to Prof. Kappos. “We have to adapt and further develop our concepts, we have to develop criteria for phase- and cause-adaptive differential indications, and we have to further explore benefits and risks of new compounds … with additional phase III-B and IV studies…. Future research will focus on the interactions of microglia and their role in the development of disability and deficits in MS.

“Investigator-initiated and publicly funded prospective and comprehensive observational and cohort studies must increasingly complement the current paradigm of mostly corporate-sponsored clinical trials,” Prof. Kappos concluded.  

—Ariel Jones  

Epilepsy Surgery Reduces Seizures At 10 Years
One decade after undergoing epilepsy surgery, about half of patients remain free of all seizures except simple partial seizures (SPS), researchers reported iLiterature Monitorn the October 15 issue of Lancet.

Jane de Tisi, of the National Hospital for Neurology and Neurosurgery, London, and colleagues followed 615 adult patients for a median of eight years after epilepsy surgery. Of these patients, 497 had anterior temporal resection, 40 had temporal lesionectomy, 40 had extratemporal lesionectomy, 20 had extratemporal resection, 11 had hemispherectomy, and seven had a palliative procedure.

Freedom from non-SPS seizures occurred in 52% of patients at five years and 47% of patients at 10 years. Eighty-two percent of patients had at least one year of freedom from non-SPS seizures, and 73% of patients had at least one year of freedom from all seizures, including SPS.

Patients who experienced SPS within two years following surgery were twice as likely as other patients to experience subsequent seizures with impaired awareness. Relapse was less likely among patients with longer periods of seizure freedom, and remission was less likely among patients with longer periods of experiencing seizures. Seizure recurrence was twice as likely in patients with extratemporal resections as in patients with anterior temporal resections.

Late seizure remission was associated with the use of a previously unused antiepileptic drug in 18 (19%) of 93 patients who experienced such a remission following initial seizures or transient relapse. Of the 365 patients who were seizure-free at their latest follow-up, 104 (28%) had discontinued use of antiepileptic drugs.

“For seizure outcome, surgery is successful for many individuals in whom antiepileptic drugs have not been effective, but further improvements need to be made to presurgical assessment to further increase rates of success,” the investigators concluded. The predictive value of SPS following surgery “has implications for decisions to discontinue antiepileptic drugs in patients with only SPS,” added Ahmed-Ramadan Sadek, MD, and William Peter Gray, MD, both from the University of Southampton, UK, in an accompanying comment.
de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet. 2011;378(9800):1388-1395.
Sadek AR, Gray WP. Chopping and changing: long-term results of epilepsy surgery. Lancet. 2011;378(9800):1360-1362.

Biomarker Analysis and Volumetric MRI Strengthen Alzheimer’s Disease Predictions
Including CSF biomarker analysis and volumetric MRI in a patient’s work-up can greatly strengthen predictions of Alzheimer’s disease, researchers reported in the October 25 Neurology.

Although cognitive impairment, abnormal CSF biomarker levels, and medial temporal atrophy predict conversion from mild cognitive impairment (MCI) to Alzheimer’s disease, routine clinical work-ups focus only on the former risk factor, noted David S. Heister, MD, PhD, of the Department of Radiology at the University of California, San Diego, and colleagues. They investigated the ability of each factor, alone or in combination, to predict such a conversion within three years among 192 patients with MCI. The researchers used the Rey Auditory Verbal Learning Test to determine learning impairment and volumetric MRI to determine medial temporal atrophy.

The combined presence of any two of the three risk factors increased Alzheimer’s disease risk substantially, they found. A combination of learning impairment and medial temporal atrophy indicated the highest risk: 85% of patients with these factors, compared with 5% of patients with neither factor, were diagnosed with Alzheimer’s disease at three years. Furthermore, none of the 18 patients who tested negative for all of the risk factors, compared with 85% of the 55 patients who tested positive for all of the risk factors, developed Alzheimer’s disease. Of the risk factors, atrophy was associated with the worst median duration of dementia-free survival, at 25 months.

“The improved predictive prognostic information available from combined use of these measures argues strongly for their inclusion in the clinical investigation of suspected Alzheimer’s disease,” the researchers concluded. “Evidence of negative CSF or negative atrophy risk factors, with relatively intact learning ability, may allow a clinician to offer reassurance to patients with MCI that the likelihood of progressing to Alzheimer’s disease in the near term is small.… In contrast, a more aggressive course of treatment and care planning would be called for when either atrophy or CSF risk factors are present.”
Heister D, Brewer JB, Magda S, et al; the Alzheimer’s Disease Neuroimaging Initiative. Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology. 2011;77(17):1619-1628.

Higher Doses of Vitamin D May Not Prevent More Lesions in Patients With MS
High doses of vitamin D2 showed no advantage compared with low doses of the vitamin in preventing or reducing brain lesions among patients with relapsing-remitting multiple sclerosis (MS), researchers reported in the October 25 Neurology.

Mark S. Stein, PhD, of Royal Melbourne Hospital, and colleagues performed a six-month randomized, controlled trial that included 23 patients with relapsing-remitting MS. Eleven patients were randomized to receive a high dose of vitamin D2 (6,000 IU), which was intended to elevate their serum 25-hydroxyvitamin D (250HD) to a level of 130 to 175 nM, while 12 patients were randomized to receive a placebo in place of the high dose. In addition, all patients received low doses of vitamin D2 (1,000 IU) to prevent deficiency.

During the follow-up period, patients underwent brain MRI and biochemical and clinical monitoring. The study’s primary end points were the cumulative number of new gadolinium-enhancing lesions and change in total volume of T2 lesions. Its secondary end points were scores on the Expanded Disability Status Scale (EDSS) and relapses.

After six months, the high-dose and low-dose groups did not differ significantly with regard to the development of new lesions or changes in the total volume of T2 lesions. Four patients who were in the high-dose group and two patients in the low-dose group developed new lesions, with totals of 14 new lesions in the high-dose group and 11 new lesions in the low-dose group. Patients in the high-dose group lost a median of 330 mm3 in lesion volume, and patients in the low-dose group lost a median of 95 mm3 of lesion volume.

Exit scores on the EDSS, after adjustment for entry scores on the scale, were marginally higher in the high-dose group than in the low-dose group. The median scores were 3 and 2 in the high-dose and low-dose groups, respectively. Four (36.5%) patients in the high-dose group and no patients in the low-dose group had a relapse.

It is possible that “any vitamin D benefit for MS occurs with low-level supplementation and oral vitamin D beyond that does not provide additional benefit,” the investigators speculated. “If this is the case, then epidemiologic correlations of better MS outcomes with higher serum 250HD may simply reflect the identification of people with MS who have a low probability of experiencing vitamin D deficiency.
Stein MS, Liu Y, Gray OM, et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology. 2011;77(17):1611-1618.

Epilepsy Surgery Reduces Seizures At 10 Years
One decade after undergoing epilepsy surgery, about half of patients remain free of all seizures except simple partial seizures (SPS), researchers reported iLiterature Monitorn the October 15 issue of Lancet.

Jane de Tisi, of the National Hospital for Neurology and Neurosurgery, London, and colleagues followed 615 adult patients for a median of eight years after epilepsy surgery. Of these patients, 497 had anterior temporal resection, 40 had temporal lesionectomy, 40 had extratemporal lesionectomy, 20 had extratemporal resection, 11 had hemispherectomy, and seven had a palliative procedure.

Freedom from non-SPS seizures occurred in 52% of patients at five years and 47% of patients at 10 years. Eighty-two percent of patients had at least one year of freedom from non-SPS seizures, and 73% of patients had at least one year of freedom from all seizures, including SPS.

Patients who experienced SPS within two years following surgery were twice as likely as other patients to experience subsequent seizures with impaired awareness. Relapse was less likely among patients with longer periods of seizure freedom, and remission was less likely among patients with longer periods of experiencing seizures. Seizure recurrence was twice as likely in patients with extratemporal resections as in patients with anterior temporal resections.

Late seizure remission was associated with the use of a previously unused antiepileptic drug in 18 (19%) of 93 patients who experienced such a remission following initial seizures or transient relapse. Of the 365 patients who were seizure-free at their latest follow-up, 104 (28%) had discontinued use of antiepileptic drugs.

“For seizure outcome, surgery is successful for many individuals in whom antiepileptic drugs have not been effective, but further improvements need to be made to presurgical assessment to further increase rates of success,” the investigators concluded. The predictive value of SPS following surgery “has implications for decisions to discontinue antiepileptic drugs in patients with only SPS,” added Ahmed-Ramadan Sadek, MD, and William Peter Gray, MD, both from the University of Southampton, UK, in an accompanying comment.
de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet. 2011;378(9800):1388-1395.
Sadek AR, Gray WP. Chopping and changing: long-term results of epilepsy surgery. Lancet. 2011;378(9800):1360-1362.

Biomarker Analysis and Volumetric MRI Strengthen Alzheimer’s Disease Predictions
Including CSF biomarker analysis and volumetric MRI in a patient’s work-up can greatly strengthen predictions of Alzheimer’s disease, researchers reported in the October 25 Neurology.

Although cognitive impairment, abnormal CSF biomarker levels, and medial temporal atrophy predict conversion from mild cognitive impairment (MCI) to Alzheimer’s disease, routine clinical work-ups focus only on the former risk factor, noted David S. Heister, MD, PhD, of the Department of Radiology at the University of California, San Diego, and colleagues. They investigated the ability of each factor, alone or in combination, to predict such a conversion within three years among 192 patients with MCI. The researchers used the Rey Auditory Verbal Learning Test to determine learning impairment and volumetric MRI to determine medial temporal atrophy.

The combined presence of any two of the three risk factors increased Alzheimer’s disease risk substantially, they found. A combination of learning impairment and medial temporal atrophy indicated the highest risk: 85% of patients with these factors, compared with 5% of patients with neither factor, were diagnosed with Alzheimer’s disease at three years. Furthermore, none of the 18 patients who tested negative for all of the risk factors, compared with 85% of the 55 patients who tested positive for all of the risk factors, developed Alzheimer’s disease. Of the risk factors, atrophy was associated with the worst median duration of dementia-free survival, at 25 months.

“The improved predictive prognostic information available from combined use of these measures argues strongly for their inclusion in the clinical investigation of suspected Alzheimer’s disease,” the researchers concluded. “Evidence of negative CSF or negative atrophy risk factors, with relatively intact learning ability, may allow a clinician to offer reassurance to patients with MCI that the likelihood of progressing to Alzheimer’s disease in the near term is small.… In contrast, a more aggressive course of treatment and care planning would be called for when either atrophy or CSF risk factors are present.”
Heister D, Brewer JB, Magda S, et al; the Alzheimer’s Disease Neuroimaging Initiative. Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology. 2011;77(17):1619-1628.

Higher Doses of Vitamin D May Not Prevent More Lesions in Patients With MS
High doses of vitamin D2 showed no advantage compared with low doses of the vitamin in preventing or reducing brain lesions among patients with relapsing-remitting multiple sclerosis (MS), researchers reported in the October 25 Neurology.

Mark S. Stein, PhD, of Royal Melbourne Hospital, and colleagues performed a six-month randomized, controlled trial that included 23 patients with relapsing-remitting MS. Eleven patients were randomized to receive a high dose of vitamin D2 (6,000 IU), which was intended to elevate their serum 25-hydroxyvitamin D (250HD) to a level of 130 to 175 nM, while 12 patients were randomized to receive a placebo in place of the high dose. In addition, all patients received low doses of vitamin D2 (1,000 IU) to prevent deficiency.

During the follow-up period, patients underwent brain MRI and biochemical and clinical monitoring. The study’s primary end points were the cumulative number of new gadolinium-enhancing lesions and change in total volume of T2 lesions. Its secondary end points were scores on the Expanded Disability Status Scale (EDSS) and relapses.

After six months, the high-dose and low-dose groups did not differ significantly with regard to the development of new lesions or changes in the total volume of T2 lesions. Four patients who were in the high-dose group and two patients in the low-dose group developed new lesions, with totals of 14 new lesions in the high-dose group and 11 new lesions in the low-dose group. Patients in the high-dose group lost a median of 330 mm3 in lesion volume, and patients in the low-dose group lost a median of 95 mm3 of lesion volume.

Exit scores on the EDSS, after adjustment for entry scores on the scale, were marginally higher in the high-dose group than in the low-dose group. The median scores were 3 and 2 in the high-dose and low-dose groups, respectively. Four (36.5%) patients in the high-dose group and no patients in the low-dose group had a relapse.

It is possible that “any vitamin D benefit for MS occurs with low-level supplementation and oral vitamin D beyond that does not provide additional benefit,” the investigators speculated. “If this is the case, then epidemiologic correlations of better MS outcomes with higher serum 250HD may simply reflect the identification of people with MS who have a low probability of experiencing vitamin D deficiency.
Stein MS, Liu Y, Gray OM, et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology. 2011;77(17):1611-1618.

Epilepsy Surgery Reduces Seizures At 10 Years
One decade after undergoing epilepsy surgery, about half of patients remain free of all seizures except simple partial seizures (SPS), researchers reported iLiterature Monitorn the October 15 issue of Lancet.

Jane de Tisi, of the National Hospital for Neurology and Neurosurgery, London, and colleagues followed 615 adult patients for a median of eight years after epilepsy surgery. Of these patients, 497 had anterior temporal resection, 40 had temporal lesionectomy, 40 had extratemporal lesionectomy, 20 had extratemporal resection, 11 had hemispherectomy, and seven had a palliative procedure.

Freedom from non-SPS seizures occurred in 52% of patients at five years and 47% of patients at 10 years. Eighty-two percent of patients had at least one year of freedom from non-SPS seizures, and 73% of patients had at least one year of freedom from all seizures, including SPS.

Patients who experienced SPS within two years following surgery were twice as likely as other patients to experience subsequent seizures with impaired awareness. Relapse was less likely among patients with longer periods of seizure freedom, and remission was less likely among patients with longer periods of experiencing seizures. Seizure recurrence was twice as likely in patients with extratemporal resections as in patients with anterior temporal resections.

Late seizure remission was associated with the use of a previously unused antiepileptic drug in 18 (19%) of 93 patients who experienced such a remission following initial seizures or transient relapse. Of the 365 patients who were seizure-free at their latest follow-up, 104 (28%) had discontinued use of antiepileptic drugs.

“For seizure outcome, surgery is successful for many individuals in whom antiepileptic drugs have not been effective, but further improvements need to be made to presurgical assessment to further increase rates of success,” the investigators concluded. The predictive value of SPS following surgery “has implications for decisions to discontinue antiepileptic drugs in patients with only SPS,” added Ahmed-Ramadan Sadek, MD, and William Peter Gray, MD, both from the University of Southampton, UK, in an accompanying comment.
de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet. 2011;378(9800):1388-1395.
Sadek AR, Gray WP. Chopping and changing: long-term results of epilepsy surgery. Lancet. 2011;378(9800):1360-1362.

Biomarker Analysis and Volumetric MRI Strengthen Alzheimer’s Disease Predictions
Including CSF biomarker analysis and volumetric MRI in a patient’s work-up can greatly strengthen predictions of Alzheimer’s disease, researchers reported in the October 25 Neurology.

Although cognitive impairment, abnormal CSF biomarker levels, and medial temporal atrophy predict conversion from mild cognitive impairment (MCI) to Alzheimer’s disease, routine clinical work-ups focus only on the former risk factor, noted David S. Heister, MD, PhD, of the Department of Radiology at the University of California, San Diego, and colleagues. They investigated the ability of each factor, alone or in combination, to predict such a conversion within three years among 192 patients with MCI. The researchers used the Rey Auditory Verbal Learning Test to determine learning impairment and volumetric MRI to determine medial temporal atrophy.

The combined presence of any two of the three risk factors increased Alzheimer’s disease risk substantially, they found. A combination of learning impairment and medial temporal atrophy indicated the highest risk: 85% of patients with these factors, compared with 5% of patients with neither factor, were diagnosed with Alzheimer’s disease at three years. Furthermore, none of the 18 patients who tested negative for all of the risk factors, compared with 85% of the 55 patients who tested positive for all of the risk factors, developed Alzheimer’s disease. Of the risk factors, atrophy was associated with the worst median duration of dementia-free survival, at 25 months.

“The improved predictive prognostic information available from combined use of these measures argues strongly for their inclusion in the clinical investigation of suspected Alzheimer’s disease,” the researchers concluded. “Evidence of negative CSF or negative atrophy risk factors, with relatively intact learning ability, may allow a clinician to offer reassurance to patients with MCI that the likelihood of progressing to Alzheimer’s disease in the near term is small.… In contrast, a more aggressive course of treatment and care planning would be called for when either atrophy or CSF risk factors are present.”
Heister D, Brewer JB, Magda S, et al; the Alzheimer’s Disease Neuroimaging Initiative. Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology. 2011;77(17):1619-1628.

Higher Doses of Vitamin D May Not Prevent More Lesions in Patients With MS
High doses of vitamin D2 showed no advantage compared with low doses of the vitamin in preventing or reducing brain lesions among patients with relapsing-remitting multiple sclerosis (MS), researchers reported in the October 25 Neurology.

Mark S. Stein, PhD, of Royal Melbourne Hospital, and colleagues performed a six-month randomized, controlled trial that included 23 patients with relapsing-remitting MS. Eleven patients were randomized to receive a high dose of vitamin D2 (6,000 IU), which was intended to elevate their serum 25-hydroxyvitamin D (250HD) to a level of 130 to 175 nM, while 12 patients were randomized to receive a placebo in place of the high dose. In addition, all patients received low doses of vitamin D2 (1,000 IU) to prevent deficiency.

During the follow-up period, patients underwent brain MRI and biochemical and clinical monitoring. The study’s primary end points were the cumulative number of new gadolinium-enhancing lesions and change in total volume of T2 lesions. Its secondary end points were scores on the Expanded Disability Status Scale (EDSS) and relapses.

After six months, the high-dose and low-dose groups did not differ significantly with regard to the development of new lesions or changes in the total volume of T2 lesions. Four patients who were in the high-dose group and two patients in the low-dose group developed new lesions, with totals of 14 new lesions in the high-dose group and 11 new lesions in the low-dose group. Patients in the high-dose group lost a median of 330 mm3 in lesion volume, and patients in the low-dose group lost a median of 95 mm3 of lesion volume.

Exit scores on the EDSS, after adjustment for entry scores on the scale, were marginally higher in the high-dose group than in the low-dose group. The median scores were 3 and 2 in the high-dose and low-dose groups, respectively. Four (36.5%) patients in the high-dose group and no patients in the low-dose group had a relapse.

It is possible that “any vitamin D benefit for MS occurs with low-level supplementation and oral vitamin D beyond that does not provide additional benefit,” the investigators speculated. “If this is the case, then epidemiologic correlations of better MS outcomes with higher serum 250HD may simply reflect the identification of people with MS who have a low probability of experiencing vitamin D deficiency.
Stein MS, Liu Y, Gray OM, et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology. 2011;77(17):1611-1618.

Researchers compare brain atrophy, T2 lesion volume, T1 lesion volume, and corpus callosum atrophy to determine the optimal MRI marker for predicting future clinical disability.

SAN DIEGO—Atrophy of the corpus callosum in the initial year among patients with multiple sclerosis (MS) may be a simple and reliable predictor of long-term disability progression, researchers reported at the 136th Annual Meeting of the American Neurological Association.

The investigators’ findings showed that the corpus callosum, compared with brain atrophy, T2 lesion volume, and T1 lesion volume, allowed them to best distinguish patients who remained stable from those with sustained progression, according to Manuela Vaneckova, MD, PhD, of the Department of Radiodiagnostics, Charles University in Prague, and colleagues.

“The advantage of the measurement of the corpus callosum atrophy is in its simplicity,” stated Dr. Vaneckova. “It can be easily done manually and can be used by clinicians in routine practice.”

Measuring Long-Term Disability Progression
Distinguishing patients with MS who remain clinically stable from those who are likely to have sustained progression is an early and important part of disease management, noted Dr. Vaneckova. “This separation can be the first step toward individually tailored MS treatment,” Dr. Vaneckova stated. “Because MS can be most effectively treated at the beginning of disease, the quickness of separation is very important.”

The researchers analyzed MRI data annually for seven years for 178 patients (3,650 examinations). The data were evaluated every eight weeks in participants’ first year, as well as in the second year for some patients. The overall mean age of the cohort was 31, and 140 participants were women. The investigators used the Expanded Disability Status Scale (EDSS) to assess clinical disability at the same time that the MRI was conducted. Subjects’ median EDSS score at baseline was 1.85, and the mean disease duration was 5.36 years.

All patients were categorized into two groups—those who were clinically stable and those who had sustained progression, which was defined as deterioration by one point in EDSS score for a duration of at least six months. In the seven years of monitoring, the investigators observed 82 patients who were stable and 96 who had sustained disability progression.

An Optimal MRI Marker for MS
“Statistically significant correlation of future clinical disability (according to EDSS score) with the brain atrophy and corpus callosum atrophy was observed in our retrospective study,” reported Dr. Vaneckova. “Correlation with lesion load was lower. Stratification of both groups with lesion load value was statistically significant already at baseline, just slightly improving during the monitoring period.

“More detailed inspection of corpus callosum atrophy during the first year, and for some patients in the second year, shows that already from the fifth month both groups are significantly different. Evaluation of whole brain atrophy differentiates stable and sustained progression groups after the third year. When separating the atrophy of white matter and gray matter, we can differentiate both groups starting in year 4, or year 5, respectively.”

Researchers compare brain atrophy, T2 lesion volume, T1 lesion volume, and corpus callosum atrophy to determine the optimal MRI marker for predicting future clinical disability.

SAN DIEGO—Atrophy of the corpus callosum in the initial year among patients with multiple sclerosis (MS) may be a simple and reliable predictor of long-term disability progression, researchers reported at the 136th Annual Meeting of the American Neurological Association.

The investigators’ findings showed that the corpus callosum, compared with brain atrophy, T2 lesion volume, and T1 lesion volume, allowed them to best distinguish patients who remained stable from those with sustained progression, according to Manuela Vaneckova, MD, PhD, of the Department of Radiodiagnostics, Charles University in Prague, and colleagues.

“The advantage of the measurement of the corpus callosum atrophy is in its simplicity,” stated Dr. Vaneckova. “It can be easily done manually and can be used by clinicians in routine practice.”

Measuring Long-Term Disability Progression
Distinguishing patients with MS who remain clinically stable from those who are likely to have sustained progression is an early and important part of disease management, noted Dr. Vaneckova. “This separation can be the first step toward individually tailored MS treatment,” Dr. Vaneckova stated. “Because MS can be most effectively treated at the beginning of disease, the quickness of separation is very important.”

The researchers analyzed MRI data annually for seven years for 178 patients (3,650 examinations). The data were evaluated every eight weeks in participants’ first year, as well as in the second year for some patients. The overall mean age of the cohort was 31, and 140 participants were women. The investigators used the Expanded Disability Status Scale (EDSS) to assess clinical disability at the same time that the MRI was conducted. Subjects’ median EDSS score at baseline was 1.85, and the mean disease duration was 5.36 years.

All patients were categorized into two groups—those who were clinically stable and those who had sustained progression, which was defined as deterioration by one point in EDSS score for a duration of at least six months. In the seven years of monitoring, the investigators observed 82 patients who were stable and 96 who had sustained disability progression.

An Optimal MRI Marker for MS
“Statistically significant correlation of future clinical disability (according to EDSS score) with the brain atrophy and corpus callosum atrophy was observed in our retrospective study,” reported Dr. Vaneckova. “Correlation with lesion load was lower. Stratification of both groups with lesion load value was statistically significant already at baseline, just slightly improving during the monitoring period.

“More detailed inspection of corpus callosum atrophy during the first year, and for some patients in the second year, shows that already from the fifth month both groups are significantly different. Evaluation of whole brain atrophy differentiates stable and sustained progression groups after the third year. When separating the atrophy of white matter and gray matter, we can differentiate both groups starting in year 4, or year 5, respectively.”

Researchers compare brain atrophy, T2 lesion volume, T1 lesion volume, and corpus callosum atrophy to determine the optimal MRI marker for predicting future clinical disability.

SAN DIEGO—Atrophy of the corpus callosum in the initial year among patients with multiple sclerosis (MS) may be a simple and reliable predictor of long-term disability progression, researchers reported at the 136th Annual Meeting of the American Neurological Association.

The investigators’ findings showed that the corpus callosum, compared with brain atrophy, T2 lesion volume, and T1 lesion volume, allowed them to best distinguish patients who remained stable from those with sustained progression, according to Manuela Vaneckova, MD, PhD, of the Department of Radiodiagnostics, Charles University in Prague, and colleagues.

“The advantage of the measurement of the corpus callosum atrophy is in its simplicity,” stated Dr. Vaneckova. “It can be easily done manually and can be used by clinicians in routine practice.”

Measuring Long-Term Disability Progression
Distinguishing patients with MS who remain clinically stable from those who are likely to have sustained progression is an early and important part of disease management, noted Dr. Vaneckova. “This separation can be the first step toward individually tailored MS treatment,” Dr. Vaneckova stated. “Because MS can be most effectively treated at the beginning of disease, the quickness of separation is very important.”

The researchers analyzed MRI data annually for seven years for 178 patients (3,650 examinations). The data were evaluated every eight weeks in participants’ first year, as well as in the second year for some patients. The overall mean age of the cohort was 31, and 140 participants were women. The investigators used the Expanded Disability Status Scale (EDSS) to assess clinical disability at the same time that the MRI was conducted. Subjects’ median EDSS score at baseline was 1.85, and the mean disease duration was 5.36 years.

All patients were categorized into two groups—those who were clinically stable and those who had sustained progression, which was defined as deterioration by one point in EDSS score for a duration of at least six months. In the seven years of monitoring, the investigators observed 82 patients who were stable and 96 who had sustained disability progression.

An Optimal MRI Marker for MS
“Statistically significant correlation of future clinical disability (according to EDSS score) with the brain atrophy and corpus callosum atrophy was observed in our retrospective study,” reported Dr. Vaneckova. “Correlation with lesion load was lower. Stratification of both groups with lesion load value was statistically significant already at baseline, just slightly improving during the monitoring period.

“More detailed inspection of corpus callosum atrophy during the first year, and for some patients in the second year, shows that already from the fifth month both groups are significantly different. Evaluation of whole brain atrophy differentiates stable and sustained progression groups after the third year. When separating the atrophy of white matter and gray matter, we can differentiate both groups starting in year 4, or year 5, respectively.”

The following brief reports summarize some of the findings presented at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). Additional coverage of the ECTRIMS/ACTRIMS meeting can be found online at www.neurologyreviews.com and in upcoming issues of Neurology Reviews.

BG-12: Data From the Phase 3 DEFINE Trials
AMSTERDAM—Results from a large phase 3 trial support the potential of BG-12 (dimethyl fumarate) as an effective oral treatment for patients with relapsing-remitting multiple sclerosis (MS). According to researchers, BG-12 may have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway.

DEFINE was a randomized, double-blind, placebo-controlled, multicenter trial that evaluated the efficacy and safety of BG-12 over two years in patients with relapsing-remitting MS. Patients ages 18 to 55 with relapsing-remitting MS and an Expanded Disability Status Scale (EDSS) score of 0 to 5 (inclusive) were randomly assigned to placebo, BG-12 240 mg BID, or BG-12 240 mg TID.

All patients underwent clinical assessments at screening, baseline, and every four weeks for up to two years. The primary end point was proportion of patients relapsing at two years. Secondary efficacy end points at two years were annualized relapse rate and disability progression as measured by EDSS score.

A total of 1,234 patients were randomized—408 received placebo, 410 received BG-12 BID, and 416 received BG-12 TID. All primary and secondary end points were met. BG-12 BID and TID reduced the risk of relapse by 49% and 50%, respectively, compared with placebo at two years. Annualized relapse rate was 0.36 with placebo, and 0.17 and 0.19 with BG-12 BID and TID, corresponding to reductions of 53% and 48% for BG-12 BID and TID. The risk of confirmed 12-week disability progression was reduced by 38% for the BID dosing and by approximately 34% with TID dosing.

The overall incidence of adverse and serious adverse events was similar among the three groups.

Alemtuzumab: Phase 3 CARE-MS I Data Released
Results of a head-to-head comparison of alemtuzumab and interferon beta-1a have shown that 78% of patients with relapsing-remitting MS treated with alemtuzumab remained relapse-free for two years, compared with 58% of patients taking interferon beta-1a.

The phase 3 CARE-MS I trial compared alemtuzumab (12 mg/d IV for five days with a second 3-day IV administration one year later) to treatment with interferon beta-1a (44 mcg SC injection 3 times per week) in 581 patients with relapsing-remitting MS who had had no previous MS treatment except steroids.

Additional findings include other secondary end points that suggest positive outcomes with alemtuzumab. Improvement in the Multiple Sclerosis Functional Composite (MSFC) score was observed in alemtuzumab-treated patients compared with interferon beta-1a–treated patients (0.12 vs 0.05, mean change from baseline at year 2). Reduction in T2-hyperintense lesion volume with alemtuzumab compared to interferon beta-1a was -9.3 versus -6.5 (median percent change at year 2). Statistically significant improvement was observed for alemtuzumab versus interferon beta-1a in the percentage of patients with new enlarging T2-hyperintense lesions (49% vs 58%), with new gadolinium-enhancing lesions (15% vs 27%), and with new T1-hypointense lesions (24% vs 31%). Alemtuzumab-treated patients also experienced less change in brain parenchymal fraction compared to interferon beta-1a (-0.87 vs -1.49, median change from baseline).

Common adverse events associated with alemtuzumab in the CARE-MS I trial were infusion-associated reactions that were mild to moderate. The incidence of infection was increased, with the most common infections involving the upper respiratory and urinary tract and oral herpes. Infections were mild to moderate, and none were life-threatening or fatal.

Serious adverse events were similar between both groups (18.4% for alemtuzumab and 14.4% for interferon beta-1a). Just over 18% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event, and 0.8% developed immune thrombocytopenia during the two-year study period. Cases of autoimmunity were detected and managed using conventional therapies.

Daclizumab: Phase 3 SELECT Trial Results Released
Monthly subcutaneous daclizumab monotherapy demonstrated a robust and clinically meaningful effect on MS activity, including evidence for early impact on disability progression, according to phase 3 data that were presented.

Researchers randomized 600 patients with relapsing-remitting MS and at least one MS relapse in the prior 12 months or one new gadolinium-enhancing lesion in the prior six weeks to receive low-dose daclizumab (150 mg), high-dose daclizumab (300 mg), or placebo as a subcutaneous injection once every four weeks for 52 weeks.

A total of 559 patients (93%) completed the treatment period. Annualized relapse rate, the study’s primary end point, was 0.21 for low-dose daclizumab, 0.23 for high-dose daclizumab, and 0.46 for placebo. The proportion of relapse-free patients was 81% in the low-dose group, 80% in the high-dose group, and 64% in the placebo group. There were significant reductions in the mean number of new or newly enlarging T2 lesions at one year (2.4 for low dose, 1.7 for high dose, and 8.1 for placebo). Among 309 patients in an MRI substudy, the mean number of new gadolinium-enhancing lesions between weeks 8 through 24 was 1.5 for low-dose daclizumab, 1.0 for the high-dose group, and 4.8 for placebo. The risk of three-month sustained disability progression at one year was reduced by 57% in the low-dose group and by 43% in the high-dose group.

Serious adverse events, excluding MS relapses, occurred in 5% of the placebo group, 6% of the low-dose group, and 8% of the high-dose group. One daclizumab-treated patient died due to a complication of a psoas abscess. Serious adverse events in the daclizumab-treated patients included an increase in serious infections (2%), serious cutaneous events (1%), and elevations in liver function tests (4%).

Clinical and MRI Outcomes in Patients With MS Treated With Fingolimod
Fingolimod at an oral dose of 0.5 mg consistently improved relapse rates, disability, and MRI outcomes compared with placebo or IM interferon beta-1a in all patient subgroups with active relapsing-remitting MS, investigators reported.

Eva Havrdová, PhD, from the Department of Neurology, First Faculty of Medicine, Charles University, Prague, and colleagues reported the results of post hoc analyses from FREEDOMS and TRANSFORMS in three patient subgroups: 1) patients who received interferon beta in the year before study entry and had equal or more relapses in the year immediately before the study than in the year two years before the study; 2) patients who received interferon beta in the year before study entry and had at least one relapse in the previous year plus at least one gadolinium-enhancing T1 lesion or nine T2 lesions at baseline; or 3) treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

In FREEDOMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with placebo in all three subgroups. In TRANSFORMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with IM interferon beta-1a in groups 1 and 2. Results in group 3 (n = 27) did not reach statistical significance. In both studies fingolimod reduced the risk of disability progression versus placebo and interferon beta-1a in all subgroups.

The researchers concluded that fingolimod (0.5 mg) improved clinical outcomes compared with placebo or IM interferon beta-1a in patients with relapsing-remitting MS with high disease activity despite previous treatment and in treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

Laquinimod: A Potential Novel Oral Agent for Relapsing-Remitting MS
Both preclinical and clinical data suggest that the oral immunomodulator laquinimod holds promise for patients with relapsing-remitting MS, according to investigators.

Giancarlo Comi, MD, Professor and Chairman of the Department of Neurology and Director of the Institute of Experimental Neurology at Vita-Salute San Raffaele University, Scientific Institute San Raffaele Milan, reported that a phase 2 study demonstrated reductions of MRI-active lesions, a trend for slowing the rate of MRI-measured brain volume loss, and a favorable safety and tolerability profile. Dr. Comi also summarized findings from the multicenter, randomized, double-blind, placebo-controlled Allegro trial. In the phase 3 trial, patients received a once-daily oral dose of 0.6 mg laquinimod or placebo for 24 months.

The study met the primary end point, with laquinimod achieving a decrease in relapse rate (23% reduction). The risk for EDSS disability progression was significantly reduced (36%) compared with placebo. Rate of brain atrophy progression was reduced by 33% at month 24.

Laquinimod was well-tolerated. Adverse events were similar in both groups, with the exception of transient, reversible elevations of liver enzymes without concomitant signs of liver dysfunction in the laquinimod group.

Dr. Comi also provided an advance glimpse of findings from the BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) study. The profile of reduced annualized relapse rate, MRI-active lesions, brain-volume loss, and EDSS was similar to that seen in the Allegro study.

Teriflunomide: A Promising New Oral Therapy for Patients With Relapsing-Remitting MS
Data from TEMSO, the first pivotal phase 3 trial of teriflunomide, were reported by Paul O’Connor, FRCPC, MSc.

The two-year, double-blind study found a significant reduction in annualized relapse rates with both the 7-mg and 14-mg doses of teriflunomide compared with placebo, as well as a significant reduction in the risk of sustained disability progression in the higher dose group. Both doses showed good safety and tolerability in patients with relapsing-remitting MS. Both doses were superior to placebo on a range of MRI end points in a dose-dependent fashion.

A long-term extension of TEMSO showed that teriflunomide was well tolerated with a favorable safety profile up to six years following randomization, with no unexpected adverse events related to long-term treatment.

Dr. O’Connor, Professor of Medicine at the University of Toronto and Director of the MS Clinic at St. Michael’s Hospital in Toronto, also discussed results from an extension of the phase 2 study of teriflunomide, which has provided information on up to nine years of teriflunomide treatment. Clinical and MRI disease activity remained low during the course of this extension and treatment-related adverse events were similar to those in the initial 36-week double-blind trial.

Both the extension of the phase 2 trial and an extension of the TEMSO trial reported minimal clinical and MRI activity. A trend toward greater benefit on both clinical and MRI parameters was seen in patients who were continually treated with teriflunomide compared with placebo-treated patients who were switched to active treatment.

Natalizumab-Associated PML Survival Rates Exceed 80%
Early diagnosis through the enhanced clinical vigilance and optimal management of progressive multifocal leukoencephalopathy (PML) may improve outcomes, according to researchers.

Survival rates in excess of 80% were seen in the first 133 postmarketing natalizumab-associated PML cases, reported Ludwig Kappos, MD, from the Departments of Neurology and Biomedicine, University Hospital, Basel, Switzerland, and colleagues. Improved survival was associated with younger age (median, 43 vs 51.5) and less disability (median EDSS, 4.0 vs 5.5) at diagnosis, shorter time from symptom onset to diagnosis (mean, 40 vs 53 days), and more localized disease on brain MRI, as compared with fatal cases.

Of 159 PML cases identified in the postmarketing setting, 130 patients were still alive as of September 1, 2011 (82% survival rate). In survivors with more than six months of follow-up, 13% had mild disability, 47% had moderate disability, and 40% had severe disability.

Higher Vitamin D Levels Are Associated With Fewer Brain Lesions
Vitamin D levels are inversely associated with the risk of MS activity on brain MRI, according to researchers.

Begun in 2004, EPIC is a five-year longitudinal MS cohort study that sought to determine if vitamin D status is associated with the development of new T2 lesions or contrast-enhancing lesions on brain MRI in a cohort of patients with clinically isolated syndrome (CIS) or relapsing-remitting MS. Participants had clinical evaluations, brain MRI, and blood draws annually.

From the overall cohort, researchers evaluated patients who had a diagnosis of CIS or relapsing-remitting MS at baseline visit. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking status, and the use of MS treatments) models, annual 25-hydroxyvitamin D3 levels were evaluated for their association with the development of new T2-weighted lesions and gadolinium-enhancing T1-weighted lesions on brain MRI as well as with the occurrence of clinical relapses of MS.

A total of 469 subjects were studied and 2,362 3T brain MRI scans were acquired and analyzed. In multivariate analyses, each 10-ng/mL higher 25-hydroxyvitamin D3 level was associated with a 15% lower risk of developing a new T2 lesion and a 32% lower risk of a gadolinium-enhancing lesion. Higher vitamin D levels were associated with a lower relapse risk, although the association did not reach statistical significance.

The following brief reports summarize some of the findings presented at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). Additional coverage of the ECTRIMS/ACTRIMS meeting can be found online at www.neurologyreviews.com and in upcoming issues of Neurology Reviews.

BG-12: Data From the Phase 3 DEFINE Trials
AMSTERDAM—Results from a large phase 3 trial support the potential of BG-12 (dimethyl fumarate) as an effective oral treatment for patients with relapsing-remitting multiple sclerosis (MS). According to researchers, BG-12 may have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway.

DEFINE was a randomized, double-blind, placebo-controlled, multicenter trial that evaluated the efficacy and safety of BG-12 over two years in patients with relapsing-remitting MS. Patients ages 18 to 55 with relapsing-remitting MS and an Expanded Disability Status Scale (EDSS) score of 0 to 5 (inclusive) were randomly assigned to placebo, BG-12 240 mg BID, or BG-12 240 mg TID.

All patients underwent clinical assessments at screening, baseline, and every four weeks for up to two years. The primary end point was proportion of patients relapsing at two years. Secondary efficacy end points at two years were annualized relapse rate and disability progression as measured by EDSS score.

A total of 1,234 patients were randomized—408 received placebo, 410 received BG-12 BID, and 416 received BG-12 TID. All primary and secondary end points were met. BG-12 BID and TID reduced the risk of relapse by 49% and 50%, respectively, compared with placebo at two years. Annualized relapse rate was 0.36 with placebo, and 0.17 and 0.19 with BG-12 BID and TID, corresponding to reductions of 53% and 48% for BG-12 BID and TID. The risk of confirmed 12-week disability progression was reduced by 38% for the BID dosing and by approximately 34% with TID dosing.

The overall incidence of adverse and serious adverse events was similar among the three groups.

Alemtuzumab: Phase 3 CARE-MS I Data Released
Results of a head-to-head comparison of alemtuzumab and interferon beta-1a have shown that 78% of patients with relapsing-remitting MS treated with alemtuzumab remained relapse-free for two years, compared with 58% of patients taking interferon beta-1a.

The phase 3 CARE-MS I trial compared alemtuzumab (12 mg/d IV for five days with a second 3-day IV administration one year later) to treatment with interferon beta-1a (44 mcg SC injection 3 times per week) in 581 patients with relapsing-remitting MS who had had no previous MS treatment except steroids.

Additional findings include other secondary end points that suggest positive outcomes with alemtuzumab. Improvement in the Multiple Sclerosis Functional Composite (MSFC) score was observed in alemtuzumab-treated patients compared with interferon beta-1a–treated patients (0.12 vs 0.05, mean change from baseline at year 2). Reduction in T2-hyperintense lesion volume with alemtuzumab compared to interferon beta-1a was -9.3 versus -6.5 (median percent change at year 2). Statistically significant improvement was observed for alemtuzumab versus interferon beta-1a in the percentage of patients with new enlarging T2-hyperintense lesions (49% vs 58%), with new gadolinium-enhancing lesions (15% vs 27%), and with new T1-hypointense lesions (24% vs 31%). Alemtuzumab-treated patients also experienced less change in brain parenchymal fraction compared to interferon beta-1a (-0.87 vs -1.49, median change from baseline).

Common adverse events associated with alemtuzumab in the CARE-MS I trial were infusion-associated reactions that were mild to moderate. The incidence of infection was increased, with the most common infections involving the upper respiratory and urinary tract and oral herpes. Infections were mild to moderate, and none were life-threatening or fatal.

Serious adverse events were similar between both groups (18.4% for alemtuzumab and 14.4% for interferon beta-1a). Just over 18% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event, and 0.8% developed immune thrombocytopenia during the two-year study period. Cases of autoimmunity were detected and managed using conventional therapies.

Daclizumab: Phase 3 SELECT Trial Results Released
Monthly subcutaneous daclizumab monotherapy demonstrated a robust and clinically meaningful effect on MS activity, including evidence for early impact on disability progression, according to phase 3 data that were presented.

Researchers randomized 600 patients with relapsing-remitting MS and at least one MS relapse in the prior 12 months or one new gadolinium-enhancing lesion in the prior six weeks to receive low-dose daclizumab (150 mg), high-dose daclizumab (300 mg), or placebo as a subcutaneous injection once every four weeks for 52 weeks.

A total of 559 patients (93%) completed the treatment period. Annualized relapse rate, the study’s primary end point, was 0.21 for low-dose daclizumab, 0.23 for high-dose daclizumab, and 0.46 for placebo. The proportion of relapse-free patients was 81% in the low-dose group, 80% in the high-dose group, and 64% in the placebo group. There were significant reductions in the mean number of new or newly enlarging T2 lesions at one year (2.4 for low dose, 1.7 for high dose, and 8.1 for placebo). Among 309 patients in an MRI substudy, the mean number of new gadolinium-enhancing lesions between weeks 8 through 24 was 1.5 for low-dose daclizumab, 1.0 for the high-dose group, and 4.8 for placebo. The risk of three-month sustained disability progression at one year was reduced by 57% in the low-dose group and by 43% in the high-dose group.

Serious adverse events, excluding MS relapses, occurred in 5% of the placebo group, 6% of the low-dose group, and 8% of the high-dose group. One daclizumab-treated patient died due to a complication of a psoas abscess. Serious adverse events in the daclizumab-treated patients included an increase in serious infections (2%), serious cutaneous events (1%), and elevations in liver function tests (4%).

Clinical and MRI Outcomes in Patients With MS Treated With Fingolimod
Fingolimod at an oral dose of 0.5 mg consistently improved relapse rates, disability, and MRI outcomes compared with placebo or IM interferon beta-1a in all patient subgroups with active relapsing-remitting MS, investigators reported.

Eva Havrdová, PhD, from the Department of Neurology, First Faculty of Medicine, Charles University, Prague, and colleagues reported the results of post hoc analyses from FREEDOMS and TRANSFORMS in three patient subgroups: 1) patients who received interferon beta in the year before study entry and had equal or more relapses in the year immediately before the study than in the year two years before the study; 2) patients who received interferon beta in the year before study entry and had at least one relapse in the previous year plus at least one gadolinium-enhancing T1 lesion or nine T2 lesions at baseline; or 3) treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

In FREEDOMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with placebo in all three subgroups. In TRANSFORMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with IM interferon beta-1a in groups 1 and 2. Results in group 3 (n = 27) did not reach statistical significance. In both studies fingolimod reduced the risk of disability progression versus placebo and interferon beta-1a in all subgroups.

The researchers concluded that fingolimod (0.5 mg) improved clinical outcomes compared with placebo or IM interferon beta-1a in patients with relapsing-remitting MS with high disease activity despite previous treatment and in treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

Laquinimod: A Potential Novel Oral Agent for Relapsing-Remitting MS
Both preclinical and clinical data suggest that the oral immunomodulator laquinimod holds promise for patients with relapsing-remitting MS, according to investigators.

Giancarlo Comi, MD, Professor and Chairman of the Department of Neurology and Director of the Institute of Experimental Neurology at Vita-Salute San Raffaele University, Scientific Institute San Raffaele Milan, reported that a phase 2 study demonstrated reductions of MRI-active lesions, a trend for slowing the rate of MRI-measured brain volume loss, and a favorable safety and tolerability profile. Dr. Comi also summarized findings from the multicenter, randomized, double-blind, placebo-controlled Allegro trial. In the phase 3 trial, patients received a once-daily oral dose of 0.6 mg laquinimod or placebo for 24 months.

The study met the primary end point, with laquinimod achieving a decrease in relapse rate (23% reduction). The risk for EDSS disability progression was significantly reduced (36%) compared with placebo. Rate of brain atrophy progression was reduced by 33% at month 24.

Laquinimod was well-tolerated. Adverse events were similar in both groups, with the exception of transient, reversible elevations of liver enzymes without concomitant signs of liver dysfunction in the laquinimod group.

Dr. Comi also provided an advance glimpse of findings from the BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) study. The profile of reduced annualized relapse rate, MRI-active lesions, brain-volume loss, and EDSS was similar to that seen in the Allegro study.

Teriflunomide: A Promising New Oral Therapy for Patients With Relapsing-Remitting MS
Data from TEMSO, the first pivotal phase 3 trial of teriflunomide, were reported by Paul O’Connor, FRCPC, MSc.

The two-year, double-blind study found a significant reduction in annualized relapse rates with both the 7-mg and 14-mg doses of teriflunomide compared with placebo, as well as a significant reduction in the risk of sustained disability progression in the higher dose group. Both doses showed good safety and tolerability in patients with relapsing-remitting MS. Both doses were superior to placebo on a range of MRI end points in a dose-dependent fashion.

A long-term extension of TEMSO showed that teriflunomide was well tolerated with a favorable safety profile up to six years following randomization, with no unexpected adverse events related to long-term treatment.

Dr. O’Connor, Professor of Medicine at the University of Toronto and Director of the MS Clinic at St. Michael’s Hospital in Toronto, also discussed results from an extension of the phase 2 study of teriflunomide, which has provided information on up to nine years of teriflunomide treatment. Clinical and MRI disease activity remained low during the course of this extension and treatment-related adverse events were similar to those in the initial 36-week double-blind trial.

Both the extension of the phase 2 trial and an extension of the TEMSO trial reported minimal clinical and MRI activity. A trend toward greater benefit on both clinical and MRI parameters was seen in patients who were continually treated with teriflunomide compared with placebo-treated patients who were switched to active treatment.

Natalizumab-Associated PML Survival Rates Exceed 80%
Early diagnosis through the enhanced clinical vigilance and optimal management of progressive multifocal leukoencephalopathy (PML) may improve outcomes, according to researchers.

Survival rates in excess of 80% were seen in the first 133 postmarketing natalizumab-associated PML cases, reported Ludwig Kappos, MD, from the Departments of Neurology and Biomedicine, University Hospital, Basel, Switzerland, and colleagues. Improved survival was associated with younger age (median, 43 vs 51.5) and less disability (median EDSS, 4.0 vs 5.5) at diagnosis, shorter time from symptom onset to diagnosis (mean, 40 vs 53 days), and more localized disease on brain MRI, as compared with fatal cases.

Of 159 PML cases identified in the postmarketing setting, 130 patients were still alive as of September 1, 2011 (82% survival rate). In survivors with more than six months of follow-up, 13% had mild disability, 47% had moderate disability, and 40% had severe disability.

Higher Vitamin D Levels Are Associated With Fewer Brain Lesions
Vitamin D levels are inversely associated with the risk of MS activity on brain MRI, according to researchers.

Begun in 2004, EPIC is a five-year longitudinal MS cohort study that sought to determine if vitamin D status is associated with the development of new T2 lesions or contrast-enhancing lesions on brain MRI in a cohort of patients with clinically isolated syndrome (CIS) or relapsing-remitting MS. Participants had clinical evaluations, brain MRI, and blood draws annually.

From the overall cohort, researchers evaluated patients who had a diagnosis of CIS or relapsing-remitting MS at baseline visit. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking status, and the use of MS treatments) models, annual 25-hydroxyvitamin D3 levels were evaluated for their association with the development of new T2-weighted lesions and gadolinium-enhancing T1-weighted lesions on brain MRI as well as with the occurrence of clinical relapses of MS.

A total of 469 subjects were studied and 2,362 3T brain MRI scans were acquired and analyzed. In multivariate analyses, each 10-ng/mL higher 25-hydroxyvitamin D3 level was associated with a 15% lower risk of developing a new T2 lesion and a 32% lower risk of a gadolinium-enhancing lesion. Higher vitamin D levels were associated with a lower relapse risk, although the association did not reach statistical significance.

The following brief reports summarize some of the findings presented at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). Additional coverage of the ECTRIMS/ACTRIMS meeting can be found online at www.neurologyreviews.com and in upcoming issues of Neurology Reviews.

BG-12: Data From the Phase 3 DEFINE Trials
AMSTERDAM—Results from a large phase 3 trial support the potential of BG-12 (dimethyl fumarate) as an effective oral treatment for patients with relapsing-remitting multiple sclerosis (MS). According to researchers, BG-12 may have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway.

DEFINE was a randomized, double-blind, placebo-controlled, multicenter trial that evaluated the efficacy and safety of BG-12 over two years in patients with relapsing-remitting MS. Patients ages 18 to 55 with relapsing-remitting MS and an Expanded Disability Status Scale (EDSS) score of 0 to 5 (inclusive) were randomly assigned to placebo, BG-12 240 mg BID, or BG-12 240 mg TID.

All patients underwent clinical assessments at screening, baseline, and every four weeks for up to two years. The primary end point was proportion of patients relapsing at two years. Secondary efficacy end points at two years were annualized relapse rate and disability progression as measured by EDSS score.

A total of 1,234 patients were randomized—408 received placebo, 410 received BG-12 BID, and 416 received BG-12 TID. All primary and secondary end points were met. BG-12 BID and TID reduced the risk of relapse by 49% and 50%, respectively, compared with placebo at two years. Annualized relapse rate was 0.36 with placebo, and 0.17 and 0.19 with BG-12 BID and TID, corresponding to reductions of 53% and 48% for BG-12 BID and TID. The risk of confirmed 12-week disability progression was reduced by 38% for the BID dosing and by approximately 34% with TID dosing.

The overall incidence of adverse and serious adverse events was similar among the three groups.

Alemtuzumab: Phase 3 CARE-MS I Data Released
Results of a head-to-head comparison of alemtuzumab and interferon beta-1a have shown that 78% of patients with relapsing-remitting MS treated with alemtuzumab remained relapse-free for two years, compared with 58% of patients taking interferon beta-1a.

The phase 3 CARE-MS I trial compared alemtuzumab (12 mg/d IV for five days with a second 3-day IV administration one year later) to treatment with interferon beta-1a (44 mcg SC injection 3 times per week) in 581 patients with relapsing-remitting MS who had had no previous MS treatment except steroids.

Additional findings include other secondary end points that suggest positive outcomes with alemtuzumab. Improvement in the Multiple Sclerosis Functional Composite (MSFC) score was observed in alemtuzumab-treated patients compared with interferon beta-1a–treated patients (0.12 vs 0.05, mean change from baseline at year 2). Reduction in T2-hyperintense lesion volume with alemtuzumab compared to interferon beta-1a was -9.3 versus -6.5 (median percent change at year 2). Statistically significant improvement was observed for alemtuzumab versus interferon beta-1a in the percentage of patients with new enlarging T2-hyperintense lesions (49% vs 58%), with new gadolinium-enhancing lesions (15% vs 27%), and with new T1-hypointense lesions (24% vs 31%). Alemtuzumab-treated patients also experienced less change in brain parenchymal fraction compared to interferon beta-1a (-0.87 vs -1.49, median change from baseline).

Common adverse events associated with alemtuzumab in the CARE-MS I trial were infusion-associated reactions that were mild to moderate. The incidence of infection was increased, with the most common infections involving the upper respiratory and urinary tract and oral herpes. Infections were mild to moderate, and none were life-threatening or fatal.

Serious adverse events were similar between both groups (18.4% for alemtuzumab and 14.4% for interferon beta-1a). Just over 18% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event, and 0.8% developed immune thrombocytopenia during the two-year study period. Cases of autoimmunity were detected and managed using conventional therapies.

Daclizumab: Phase 3 SELECT Trial Results Released
Monthly subcutaneous daclizumab monotherapy demonstrated a robust and clinically meaningful effect on MS activity, including evidence for early impact on disability progression, according to phase 3 data that were presented.

Researchers randomized 600 patients with relapsing-remitting MS and at least one MS relapse in the prior 12 months or one new gadolinium-enhancing lesion in the prior six weeks to receive low-dose daclizumab (150 mg), high-dose daclizumab (300 mg), or placebo as a subcutaneous injection once every four weeks for 52 weeks.

A total of 559 patients (93%) completed the treatment period. Annualized relapse rate, the study’s primary end point, was 0.21 for low-dose daclizumab, 0.23 for high-dose daclizumab, and 0.46 for placebo. The proportion of relapse-free patients was 81% in the low-dose group, 80% in the high-dose group, and 64% in the placebo group. There were significant reductions in the mean number of new or newly enlarging T2 lesions at one year (2.4 for low dose, 1.7 for high dose, and 8.1 for placebo). Among 309 patients in an MRI substudy, the mean number of new gadolinium-enhancing lesions between weeks 8 through 24 was 1.5 for low-dose daclizumab, 1.0 for the high-dose group, and 4.8 for placebo. The risk of three-month sustained disability progression at one year was reduced by 57% in the low-dose group and by 43% in the high-dose group.

Serious adverse events, excluding MS relapses, occurred in 5% of the placebo group, 6% of the low-dose group, and 8% of the high-dose group. One daclizumab-treated patient died due to a complication of a psoas abscess. Serious adverse events in the daclizumab-treated patients included an increase in serious infections (2%), serious cutaneous events (1%), and elevations in liver function tests (4%).

Clinical and MRI Outcomes in Patients With MS Treated With Fingolimod
Fingolimod at an oral dose of 0.5 mg consistently improved relapse rates, disability, and MRI outcomes compared with placebo or IM interferon beta-1a in all patient subgroups with active relapsing-remitting MS, investigators reported.

Eva Havrdová, PhD, from the Department of Neurology, First Faculty of Medicine, Charles University, Prague, and colleagues reported the results of post hoc analyses from FREEDOMS and TRANSFORMS in three patient subgroups: 1) patients who received interferon beta in the year before study entry and had equal or more relapses in the year immediately before the study than in the year two years before the study; 2) patients who received interferon beta in the year before study entry and had at least one relapse in the previous year plus at least one gadolinium-enhancing T1 lesion or nine T2 lesions at baseline; or 3) treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

In FREEDOMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with placebo in all three subgroups. In TRANSFORMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with IM interferon beta-1a in groups 1 and 2. Results in group 3 (n = 27) did not reach statistical significance. In both studies fingolimod reduced the risk of disability progression versus placebo and interferon beta-1a in all subgroups.

The researchers concluded that fingolimod (0.5 mg) improved clinical outcomes compared with placebo or IM interferon beta-1a in patients with relapsing-remitting MS with high disease activity despite previous treatment and in treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

Laquinimod: A Potential Novel Oral Agent for Relapsing-Remitting MS
Both preclinical and clinical data suggest that the oral immunomodulator laquinimod holds promise for patients with relapsing-remitting MS, according to investigators.

Giancarlo Comi, MD, Professor and Chairman of the Department of Neurology and Director of the Institute of Experimental Neurology at Vita-Salute San Raffaele University, Scientific Institute San Raffaele Milan, reported that a phase 2 study demonstrated reductions of MRI-active lesions, a trend for slowing the rate of MRI-measured brain volume loss, and a favorable safety and tolerability profile. Dr. Comi also summarized findings from the multicenter, randomized, double-blind, placebo-controlled Allegro trial. In the phase 3 trial, patients received a once-daily oral dose of 0.6 mg laquinimod or placebo for 24 months.

The study met the primary end point, with laquinimod achieving a decrease in relapse rate (23% reduction). The risk for EDSS disability progression was significantly reduced (36%) compared with placebo. Rate of brain atrophy progression was reduced by 33% at month 24.

Laquinimod was well-tolerated. Adverse events were similar in both groups, with the exception of transient, reversible elevations of liver enzymes without concomitant signs of liver dysfunction in the laquinimod group.

Dr. Comi also provided an advance glimpse of findings from the BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) study. The profile of reduced annualized relapse rate, MRI-active lesions, brain-volume loss, and EDSS was similar to that seen in the Allegro study.

Teriflunomide: A Promising New Oral Therapy for Patients With Relapsing-Remitting MS
Data from TEMSO, the first pivotal phase 3 trial of teriflunomide, were reported by Paul O’Connor, FRCPC, MSc.

The two-year, double-blind study found a significant reduction in annualized relapse rates with both the 7-mg and 14-mg doses of teriflunomide compared with placebo, as well as a significant reduction in the risk of sustained disability progression in the higher dose group. Both doses showed good safety and tolerability in patients with relapsing-remitting MS. Both doses were superior to placebo on a range of MRI end points in a dose-dependent fashion.

A long-term extension of TEMSO showed that teriflunomide was well tolerated with a favorable safety profile up to six years following randomization, with no unexpected adverse events related to long-term treatment.

Dr. O’Connor, Professor of Medicine at the University of Toronto and Director of the MS Clinic at St. Michael’s Hospital in Toronto, also discussed results from an extension of the phase 2 study of teriflunomide, which has provided information on up to nine years of teriflunomide treatment. Clinical and MRI disease activity remained low during the course of this extension and treatment-related adverse events were similar to those in the initial 36-week double-blind trial.

Both the extension of the phase 2 trial and an extension of the TEMSO trial reported minimal clinical and MRI activity. A trend toward greater benefit on both clinical and MRI parameters was seen in patients who were continually treated with teriflunomide compared with placebo-treated patients who were switched to active treatment.

Natalizumab-Associated PML Survival Rates Exceed 80%
Early diagnosis through the enhanced clinical vigilance and optimal management of progressive multifocal leukoencephalopathy (PML) may improve outcomes, according to researchers.

Survival rates in excess of 80% were seen in the first 133 postmarketing natalizumab-associated PML cases, reported Ludwig Kappos, MD, from the Departments of Neurology and Biomedicine, University Hospital, Basel, Switzerland, and colleagues. Improved survival was associated with younger age (median, 43 vs 51.5) and less disability (median EDSS, 4.0 vs 5.5) at diagnosis, shorter time from symptom onset to diagnosis (mean, 40 vs 53 days), and more localized disease on brain MRI, as compared with fatal cases.

Of 159 PML cases identified in the postmarketing setting, 130 patients were still alive as of September 1, 2011 (82% survival rate). In survivors with more than six months of follow-up, 13% had mild disability, 47% had moderate disability, and 40% had severe disability.

Higher Vitamin D Levels Are Associated With Fewer Brain Lesions
Vitamin D levels are inversely associated with the risk of MS activity on brain MRI, according to researchers.

Begun in 2004, EPIC is a five-year longitudinal MS cohort study that sought to determine if vitamin D status is associated with the development of new T2 lesions or contrast-enhancing lesions on brain MRI in a cohort of patients with clinically isolated syndrome (CIS) or relapsing-remitting MS. Participants had clinical evaluations, brain MRI, and blood draws annually.

From the overall cohort, researchers evaluated patients who had a diagnosis of CIS or relapsing-remitting MS at baseline visit. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking status, and the use of MS treatments) models, annual 25-hydroxyvitamin D3 levels were evaluated for their association with the development of new T2-weighted lesions and gadolinium-enhancing T1-weighted lesions on brain MRI as well as with the occurrence of clinical relapses of MS.

A total of 469 subjects were studied and 2,362 3T brain MRI scans were acquired and analyzed. In multivariate analyses, each 10-ng/mL higher 25-hydroxyvitamin D3 level was associated with a 15% lower risk of developing a new T2 lesion and a 32% lower risk of a gadolinium-enhancing lesion. Higher vitamin D levels were associated with a lower relapse risk, although the association did not reach statistical significance.

Among patients with multiple sclerosis, oligoclonal bands were more common and levels of CSF protein and immunoglobulin G were higher with primary progressive disease than with relapsing-onset disease.

MONTREAL—Retrospective data indicate that primary progressive multiple sclerosis (MS) and relapsing-onset MS have different immunologic etiologies, researchers reported at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Pedro Lourenco, from the Department of Neurology at the University of British Columbia in Vancouver, and colleagues investigated whether oligoclonal band (OCB)/CSF findings are associated with disease course and progression in patients with MS. They also investigated whether ethnicity and testing bias affected such associations. The researchers performed retrospective analyses in a sample of 6,935 patients with MS who registered at the British Columbia MS Clinics between 1982 and 2010.

Among this cohort, 1,120 patients had OCB/CSF testing, and a comparison of these patients with untested patients indicated a testing bias. Male gender was more common in tested than in untested patients, at 32.2% and 27.7%, respectively. In addition, the mean age at symptom onset was 35.0 for the tested patients, versus 31.5 for the untested patients.

OCBs were detected in 694 (72.5%) of the 957 patients tested for the bands. They were detected in 107 (79.8%) of 134 patients with primary progressive MS, compared with 587 (71.3%) of the 823 patients with relapsing-onset MS. The difference between disease courses was greater among Caucasian patients—OCBs were detected in 70 (87.5%) of the 80 Caucasian patients with primary progressive disease and 360 (71.9%) of the 499 Caucasian patients with relapsing-onset disease. There were no associations between disease progression outcomes and OCB status, however.

On average, patients with primary progressive disease had total CSF immunoglobulin G levels of 64.1 mg/L, compared with 52.0 mg/L in patients with relapsing-onset disease. Average total protein levels also were higher in patients with primary progressive MS than in patients with relapsing-onset MS, at 502 mg/L and 174 mg/L, respectively.

These results suggest that there are “different immunologic etiologies for relapsing-onset and primary progressive MS,” the researchers concluded.

Among patients with multiple sclerosis, oligoclonal bands were more common and levels of CSF protein and immunoglobulin G were higher with primary progressive disease than with relapsing-onset disease.

MONTREAL—Retrospective data indicate that primary progressive multiple sclerosis (MS) and relapsing-onset MS have different immunologic etiologies, researchers reported at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Pedro Lourenco, from the Department of Neurology at the University of British Columbia in Vancouver, and colleagues investigated whether oligoclonal band (OCB)/CSF findings are associated with disease course and progression in patients with MS. They also investigated whether ethnicity and testing bias affected such associations. The researchers performed retrospective analyses in a sample of 6,935 patients with MS who registered at the British Columbia MS Clinics between 1982 and 2010.

Among this cohort, 1,120 patients had OCB/CSF testing, and a comparison of these patients with untested patients indicated a testing bias. Male gender was more common in tested than in untested patients, at 32.2% and 27.7%, respectively. In addition, the mean age at symptom onset was 35.0 for the tested patients, versus 31.5 for the untested patients.

OCBs were detected in 694 (72.5%) of the 957 patients tested for the bands. They were detected in 107 (79.8%) of 134 patients with primary progressive MS, compared with 587 (71.3%) of the 823 patients with relapsing-onset MS. The difference between disease courses was greater among Caucasian patients—OCBs were detected in 70 (87.5%) of the 80 Caucasian patients with primary progressive disease and 360 (71.9%) of the 499 Caucasian patients with relapsing-onset disease. There were no associations between disease progression outcomes and OCB status, however.

On average, patients with primary progressive disease had total CSF immunoglobulin G levels of 64.1 mg/L, compared with 52.0 mg/L in patients with relapsing-onset disease. Average total protein levels also were higher in patients with primary progressive MS than in patients with relapsing-onset MS, at 502 mg/L and 174 mg/L, respectively.

These results suggest that there are “different immunologic etiologies for relapsing-onset and primary progressive MS,” the researchers concluded.

Among patients with multiple sclerosis, oligoclonal bands were more common and levels of CSF protein and immunoglobulin G were higher with primary progressive disease than with relapsing-onset disease.

MONTREAL—Retrospective data indicate that primary progressive multiple sclerosis (MS) and relapsing-onset MS have different immunologic etiologies, researchers reported at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Pedro Lourenco, from the Department of Neurology at the University of British Columbia in Vancouver, and colleagues investigated whether oligoclonal band (OCB)/CSF findings are associated with disease course and progression in patients with MS. They also investigated whether ethnicity and testing bias affected such associations. The researchers performed retrospective analyses in a sample of 6,935 patients with MS who registered at the British Columbia MS Clinics between 1982 and 2010.

Among this cohort, 1,120 patients had OCB/CSF testing, and a comparison of these patients with untested patients indicated a testing bias. Male gender was more common in tested than in untested patients, at 32.2% and 27.7%, respectively. In addition, the mean age at symptom onset was 35.0 for the tested patients, versus 31.5 for the untested patients.

OCBs were detected in 694 (72.5%) of the 957 patients tested for the bands. They were detected in 107 (79.8%) of 134 patients with primary progressive MS, compared with 587 (71.3%) of the 823 patients with relapsing-onset MS. The difference between disease courses was greater among Caucasian patients—OCBs were detected in 70 (87.5%) of the 80 Caucasian patients with primary progressive disease and 360 (71.9%) of the 499 Caucasian patients with relapsing-onset disease. There were no associations between disease progression outcomes and OCB status, however.

On average, patients with primary progressive disease had total CSF immunoglobulin G levels of 64.1 mg/L, compared with 52.0 mg/L in patients with relapsing-onset disease. Average total protein levels also were higher in patients with primary progressive MS than in patients with relapsing-onset MS, at 502 mg/L and 174 mg/L, respectively.

These results suggest that there are “different immunologic etiologies for relapsing-onset and primary progressive MS,” the researchers concluded.

Responses to a survey of women with multiple sclerosis suggested that neither menopause nor hormone replacement therapy affected their MS symptoms.

MONTREAL—Neither menopause nor hormone replacement affects multiple sclerosis (MS) symptoms in most women with the disorder, according to survey results presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Sex hormones are believed to play a modulating role in MS, noted Annette Wundes, MD, Assistant Professor of Neurology at the University of Washington in Seattle, and colleagues. Thus, the researchers developed a mail survey to investigate whether menopause affects the clinical course of MS, whether symptoms of menopause are erroneously attributed to MS, and whether pharmacologic intervention affects either scenario. The survey asked women with MS about their age at menopause onset, the cause of their menopause, and their use of hormone replacement therapy. It also inquired into relationships between menopause, hormone replacement, and MS symptoms and disease course.

Of the 591 survey respondents, 316 (53%) were postmenopausal women with MS. Their ages at menopause onset ranged from 19 to 62, with a median age of 46—five years earlier than that of the general US population at menopause. Nearly half of the respondents with menopause said that it was induced iatrogenically. Most respondents with menopause reported no association between menopause and MS symptoms; those who did, however, were likely to report that menopause had worsened their symptoms.

Slightly more than 50% of the respondents reported that they had been treated with hormone replacement therapy, and the average duration of such therapy was five years. About 75% of the women who had been treated with hormone replacement therapy reported that the therapy had not affected their MS symptoms or the overall course of the disease.

“Data from two previous studies … suggesting benefits of hormone replacement therapy and worsening of MS with menopause were not confirmed in this sample,” the researchers concluded. “However, none of the questionnaires used, including our own, studies the full complexity of menopausal changes, effects of hormone replacement therapy, and natural changes of MS with aging. Further studies are warranted."

Responses to a survey of women with multiple sclerosis suggested that neither menopause nor hormone replacement therapy affected their MS symptoms.

MONTREAL—Neither menopause nor hormone replacement affects multiple sclerosis (MS) symptoms in most women with the disorder, according to survey results presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Sex hormones are believed to play a modulating role in MS, noted Annette Wundes, MD, Assistant Professor of Neurology at the University of Washington in Seattle, and colleagues. Thus, the researchers developed a mail survey to investigate whether menopause affects the clinical course of MS, whether symptoms of menopause are erroneously attributed to MS, and whether pharmacologic intervention affects either scenario. The survey asked women with MS about their age at menopause onset, the cause of their menopause, and their use of hormone replacement therapy. It also inquired into relationships between menopause, hormone replacement, and MS symptoms and disease course.

Of the 591 survey respondents, 316 (53%) were postmenopausal women with MS. Their ages at menopause onset ranged from 19 to 62, with a median age of 46—five years earlier than that of the general US population at menopause. Nearly half of the respondents with menopause said that it was induced iatrogenically. Most respondents with menopause reported no association between menopause and MS symptoms; those who did, however, were likely to report that menopause had worsened their symptoms.

Slightly more than 50% of the respondents reported that they had been treated with hormone replacement therapy, and the average duration of such therapy was five years. About 75% of the women who had been treated with hormone replacement therapy reported that the therapy had not affected their MS symptoms or the overall course of the disease.

“Data from two previous studies … suggesting benefits of hormone replacement therapy and worsening of MS with menopause were not confirmed in this sample,” the researchers concluded. “However, none of the questionnaires used, including our own, studies the full complexity of menopausal changes, effects of hormone replacement therapy, and natural changes of MS with aging. Further studies are warranted."

Responses to a survey of women with multiple sclerosis suggested that neither menopause nor hormone replacement therapy affected their MS symptoms.

MONTREAL—Neither menopause nor hormone replacement affects multiple sclerosis (MS) symptoms in most women with the disorder, according to survey results presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Sex hormones are believed to play a modulating role in MS, noted Annette Wundes, MD, Assistant Professor of Neurology at the University of Washington in Seattle, and colleagues. Thus, the researchers developed a mail survey to investigate whether menopause affects the clinical course of MS, whether symptoms of menopause are erroneously attributed to MS, and whether pharmacologic intervention affects either scenario. The survey asked women with MS about their age at menopause onset, the cause of their menopause, and their use of hormone replacement therapy. It also inquired into relationships between menopause, hormone replacement, and MS symptoms and disease course.

Of the 591 survey respondents, 316 (53%) were postmenopausal women with MS. Their ages at menopause onset ranged from 19 to 62, with a median age of 46—five years earlier than that of the general US population at menopause. Nearly half of the respondents with menopause said that it was induced iatrogenically. Most respondents with menopause reported no association between menopause and MS symptoms; those who did, however, were likely to report that menopause had worsened their symptoms.

Slightly more than 50% of the respondents reported that they had been treated with hormone replacement therapy, and the average duration of such therapy was five years. About 75% of the women who had been treated with hormone replacement therapy reported that the therapy had not affected their MS symptoms or the overall course of the disease.

“Data from two previous studies … suggesting benefits of hormone replacement therapy and worsening of MS with menopause were not confirmed in this sample,” the researchers concluded. “However, none of the questionnaires used, including our own, studies the full complexity of menopausal changes, effects of hormone replacement therapy, and natural changes of MS with aging. Further studies are warranted."