Multiple Sclerosis Hub

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."

Low levels of vitamin D are most likely not responsible for the fatigue, depression, and cognitive impairment experienced by patients with multiple sclerosis.

MONTREAL—Although patients with multiple sclerosis (MS) often have low serum levels of vitamin D, no significant correlation was found between this insufficiency and MS-associated fatigue, depression, or cognition, according to research presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Previous studies have reported a connection between cognitive decline and depression in the elderly, but this relationship has not been studied thoroughly in patients with MS, the investigators noted. “Fatigue, depression, and cognitive impairment are frequently present in MS, but their underlying etiologies are unclear,” they wrote. “[Our objective was] to investigate the relationship between vitamin D and fatigue, depression, and cognition in MS.”

Led by Sandra L. Cook, RN, from the Partners Multiple Sclerosis Center and Brigham and Women’s Hospital in Boston, the researchers analyzed testing results of 220 participants enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital, Partners MS Center (CLIMB). Persons enrolled in this study underwent annual neurologic examinations and completed annual psychosocial and cognitive measures, including the Modified Fatigue Impact Scale (MFIS), Center for Epidemiologic Studies Depression Scale (CESD), and Symbol Digit Modalities Test (SDMT), which measures speed of information processing and working memory. Scores on the Expanded Disability Status Scale (EDSS) were also recorded.

The study population was mostly female (73.1%) and had a mean age of 47. The majority of patients had relapsing-remitting MS (77.4%), the median EDSS score was 1.5, and the mean disease duration from symptom onset was 13.3 years.

“The mean vitamin D level in our sample was 36.4 ng/mL,” Ms. Cook and colleagues reported. “Using 30 ng/mL as a cutoff, 27.4% of subjects were insufficient. Mean scores for outcome variables were 25.4 for MFIS, 28.5 for CESD, and 55.4 for SDMT.” When the investigators examined scores on the neurologic, psychosocial, and cognitive measures, they found no significant relationships between levels of vitamin D and fatigue, depression, cognition, or EDSS score, suggesting that vitamin D insufficiency is not the underlying mechanism for these symptoms.

Low levels of vitamin D are most likely not responsible for the fatigue, depression, and cognitive impairment experienced by patients with multiple sclerosis.

MONTREAL—Although patients with multiple sclerosis (MS) often have low serum levels of vitamin D, no significant correlation was found between this insufficiency and MS-associated fatigue, depression, or cognition, according to research presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Previous studies have reported a connection between cognitive decline and depression in the elderly, but this relationship has not been studied thoroughly in patients with MS, the investigators noted. “Fatigue, depression, and cognitive impairment are frequently present in MS, but their underlying etiologies are unclear,” they wrote. “[Our objective was] to investigate the relationship between vitamin D and fatigue, depression, and cognition in MS.”

Led by Sandra L. Cook, RN, from the Partners Multiple Sclerosis Center and Brigham and Women’s Hospital in Boston, the researchers analyzed testing results of 220 participants enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital, Partners MS Center (CLIMB). Persons enrolled in this study underwent annual neurologic examinations and completed annual psychosocial and cognitive measures, including the Modified Fatigue Impact Scale (MFIS), Center for Epidemiologic Studies Depression Scale (CESD), and Symbol Digit Modalities Test (SDMT), which measures speed of information processing and working memory. Scores on the Expanded Disability Status Scale (EDSS) were also recorded.

The study population was mostly female (73.1%) and had a mean age of 47. The majority of patients had relapsing-remitting MS (77.4%), the median EDSS score was 1.5, and the mean disease duration from symptom onset was 13.3 years.

“The mean vitamin D level in our sample was 36.4 ng/mL,” Ms. Cook and colleagues reported. “Using 30 ng/mL as a cutoff, 27.4% of subjects were insufficient. Mean scores for outcome variables were 25.4 for MFIS, 28.5 for CESD, and 55.4 for SDMT.” When the investigators examined scores on the neurologic, psychosocial, and cognitive measures, they found no significant relationships between levels of vitamin D and fatigue, depression, cognition, or EDSS score, suggesting that vitamin D insufficiency is not the underlying mechanism for these symptoms.

Low levels of vitamin D are most likely not responsible for the fatigue, depression, and cognitive impairment experienced by patients with multiple sclerosis.

MONTREAL—Although patients with multiple sclerosis (MS) often have low serum levels of vitamin D, no significant correlation was found between this insufficiency and MS-associated fatigue, depression, or cognition, according to research presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Previous studies have reported a connection between cognitive decline and depression in the elderly, but this relationship has not been studied thoroughly in patients with MS, the investigators noted. “Fatigue, depression, and cognitive impairment are frequently present in MS, but their underlying etiologies are unclear,” they wrote. “[Our objective was] to investigate the relationship between vitamin D and fatigue, depression, and cognition in MS.”

Led by Sandra L. Cook, RN, from the Partners Multiple Sclerosis Center and Brigham and Women’s Hospital in Boston, the researchers analyzed testing results of 220 participants enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women’s Hospital, Partners MS Center (CLIMB). Persons enrolled in this study underwent annual neurologic examinations and completed annual psychosocial and cognitive measures, including the Modified Fatigue Impact Scale (MFIS), Center for Epidemiologic Studies Depression Scale (CESD), and Symbol Digit Modalities Test (SDMT), which measures speed of information processing and working memory. Scores on the Expanded Disability Status Scale (EDSS) were also recorded.

The study population was mostly female (73.1%) and had a mean age of 47. The majority of patients had relapsing-remitting MS (77.4%), the median EDSS score was 1.5, and the mean disease duration from symptom onset was 13.3 years.

“The mean vitamin D level in our sample was 36.4 ng/mL,” Ms. Cook and colleagues reported. “Using 30 ng/mL as a cutoff, 27.4% of subjects were insufficient. Mean scores for outcome variables were 25.4 for MFIS, 28.5 for CESD, and 55.4 for SDMT.” When the investigators examined scores on the neurologic, psychosocial, and cognitive measures, they found no significant relationships between levels of vitamin D and fatigue, depression, cognition, or EDSS score, suggesting that vitamin D insufficiency is not the underlying mechanism for these symptoms.

Among a sample of 12,386,144 hospitalized patients, those with MS were over 10 years younger than those with diabetes or from the general hospitalized population, on average, when they experienced in-hospital death.

MONTREAL—On average, patients with MS are over 10 years younger than  patients with diabetes mellitus (DM) and patients in the general hospitalized population (GHP) when they experience in-hospital death, researchers reported at 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Frank R. Ernst, PharmD, MS, of Premier Healthcare Alliance, Charlotte, North Carolina, and colleagues noted a paucity of research on mortality and the comorbidities that contribute to it in patients with MS. To investigate these issues, they used a database of information from 600 US hospitals collected over a three-year period to gather data on 12,386,144 patients—110,045 with MS, 4,013,483 with DM, and 8,262,616 from the GHP (who had neither MS nor DM). Then they compared diagnoses, covariates, and comorbidities among the three patient groups.

The patients with MS had the lowest unadjusted gross mortality rate, with in-hospital deaths occurring in 1,336 (1.2%) of these patients, compared with 123,322 (3.1%) patients with DM and 247,799 (3.0%) in GHP patients. The lower MS morality rate is “a possible consequence of restricting the analysis to in-hospital deaths and to lack of adjustments for other covariates,” according to the researchers.

The mean ages at hospital admission were 50.3 in the MS group, 63.1 in the DM group, and 54.3 in the GHP group. The mean ages at in-hospital death were 62.8, 72.9, and 73.1 in the MS, DM, and GHP groups, respectively. The “significantly 10-year lower mean age at death for MS versus DM or GHP… may be related to the significantly earlier mean age at admission,” the researchers suggested.

The most common principal diagnosis associated with death in all three groups was septicemia/sepsis/shock, which accounted for 30%, 18.5%, and 16.4% of deaths in the MS, DM, and GHP groups, respectively. The percentages of deaths in the MS, DM, and GHP accounted for by all eight of the primary diagnosis categories identified by the researchers are shown in the Table.

Percentage of Deaths Within Patient Groups Accounted for by Principle Diagnosis

“While the majority of patients were not treated directly for MS, the hospital care received was a likely consequence of underlying MS in many,” the researchers concluded. “This may explain the lower proportion of deaths with principal diagnoses associated with MS … relative to previous studies, which used different ascertainment methods.”

Among a sample of 12,386,144 hospitalized patients, those with MS were over 10 years younger than those with diabetes or from the general hospitalized population, on average, when they experienced in-hospital death.

MONTREAL—On average, patients with MS are over 10 years younger than  patients with diabetes mellitus (DM) and patients in the general hospitalized population (GHP) when they experience in-hospital death, researchers reported at 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Frank R. Ernst, PharmD, MS, of Premier Healthcare Alliance, Charlotte, North Carolina, and colleagues noted a paucity of research on mortality and the comorbidities that contribute to it in patients with MS. To investigate these issues, they used a database of information from 600 US hospitals collected over a three-year period to gather data on 12,386,144 patients—110,045 with MS, 4,013,483 with DM, and 8,262,616 from the GHP (who had neither MS nor DM). Then they compared diagnoses, covariates, and comorbidities among the three patient groups.

The patients with MS had the lowest unadjusted gross mortality rate, with in-hospital deaths occurring in 1,336 (1.2%) of these patients, compared with 123,322 (3.1%) patients with DM and 247,799 (3.0%) in GHP patients. The lower MS morality rate is “a possible consequence of restricting the analysis to in-hospital deaths and to lack of adjustments for other covariates,” according to the researchers.

The mean ages at hospital admission were 50.3 in the MS group, 63.1 in the DM group, and 54.3 in the GHP group. The mean ages at in-hospital death were 62.8, 72.9, and 73.1 in the MS, DM, and GHP groups, respectively. The “significantly 10-year lower mean age at death for MS versus DM or GHP… may be related to the significantly earlier mean age at admission,” the researchers suggested.

The most common principal diagnosis associated with death in all three groups was septicemia/sepsis/shock, which accounted for 30%, 18.5%, and 16.4% of deaths in the MS, DM, and GHP groups, respectively. The percentages of deaths in the MS, DM, and GHP accounted for by all eight of the primary diagnosis categories identified by the researchers are shown in the Table.

Percentage of Deaths Within Patient Groups Accounted for by Principle Diagnosis

“While the majority of patients were not treated directly for MS, the hospital care received was a likely consequence of underlying MS in many,” the researchers concluded. “This may explain the lower proportion of deaths with principal diagnoses associated with MS … relative to previous studies, which used different ascertainment methods.”

Among a sample of 12,386,144 hospitalized patients, those with MS were over 10 years younger than those with diabetes or from the general hospitalized population, on average, when they experienced in-hospital death.

MONTREAL—On average, patients with MS are over 10 years younger than  patients with diabetes mellitus (DM) and patients in the general hospitalized population (GHP) when they experience in-hospital death, researchers reported at 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

Frank R. Ernst, PharmD, MS, of Premier Healthcare Alliance, Charlotte, North Carolina, and colleagues noted a paucity of research on mortality and the comorbidities that contribute to it in patients with MS. To investigate these issues, they used a database of information from 600 US hospitals collected over a three-year period to gather data on 12,386,144 patients—110,045 with MS, 4,013,483 with DM, and 8,262,616 from the GHP (who had neither MS nor DM). Then they compared diagnoses, covariates, and comorbidities among the three patient groups.

The patients with MS had the lowest unadjusted gross mortality rate, with in-hospital deaths occurring in 1,336 (1.2%) of these patients, compared with 123,322 (3.1%) patients with DM and 247,799 (3.0%) in GHP patients. The lower MS morality rate is “a possible consequence of restricting the analysis to in-hospital deaths and to lack of adjustments for other covariates,” according to the researchers.

The mean ages at hospital admission were 50.3 in the MS group, 63.1 in the DM group, and 54.3 in the GHP group. The mean ages at in-hospital death were 62.8, 72.9, and 73.1 in the MS, DM, and GHP groups, respectively. The “significantly 10-year lower mean age at death for MS versus DM or GHP… may be related to the significantly earlier mean age at admission,” the researchers suggested.

The most common principal diagnosis associated with death in all three groups was septicemia/sepsis/shock, which accounted for 30%, 18.5%, and 16.4% of deaths in the MS, DM, and GHP groups, respectively. The percentages of deaths in the MS, DM, and GHP accounted for by all eight of the primary diagnosis categories identified by the researchers are shown in the Table.

Percentage of Deaths Within Patient Groups Accounted for by Principle Diagnosis

“While the majority of patients were not treated directly for MS, the hospital care received was a likely consequence of underlying MS in many,” the researchers concluded. “This may explain the lower proportion of deaths with principal diagnoses associated with MS … relative to previous studies, which used different ascertainment methods.”

MONTREAL—A modified version of the Six-Minute Walk Test (6MWT) may measure walking disability in patients with multiple sclerosis (MS) more precisely than the tests currently used for this purpose, according to research presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“The 6MWT is feasible and tolerated in subjects with MS, including those in the upper Expanded Disability Status Scale (EDSS) range of 4.0 to 6.5,” said Myla Goldman, MD, of the Department of Neurology at the University of Virginia in Charlottesville. “The 6MWT and the Timed 25-Foot Walk (T25FW) are well-correlated variables, but overall, the 6MWT appears to have increased precision in identifying EDSS subgroups.”

Dr. Goldman and colleagues came to these conclusions by testing the 6MWT, which historically has been used in patients with respiratory or cardiac disease, in a cohort of 96 patients with MS.

In addition to showing greater precision than the T25FW, the 6MWT correlated fairly well with the Multiple Sclerosis Walking Scale-12 (MSWS-12), a subjective measure of MS walking disability.

The Search for an Alternative Measure
The currently accepted measures of MS walking disability all have important limitations, according to Dr. Goldman. Some patients with mild MS may have walking difficulties below the threshold detectible by the T25FW (the ambulatory component of the Multiple Sclerosis Functional Composite) or the EDSS ambulatory component, she said, adding that the EDSS’s compression of data into ordinal variables limits its sensitivity. Because the MSWS-12 depends on subjective reports from patients, she added, it needs to be considered in conjunction with more objective measures.

With these limitations in mind, the researchers turned to the 6MWT, which determines walking capacity by having subjects walk as far as they can in six minutes. The test is administered on an indoor walking course of at least 30 meters, and persons are asked to pivot and continue to walk whenever they reach an end of the course. The primary outcome is total distance walked, but other assessed outcomes can include subjects’ heart rate, dyspnea, fatigue, and oxygen saturation before and after the test; stopping or pausing during the test; and symptoms of angina, dizziness, or pain at the end of the test.

In a 2008 study, Dr. Goldman and colleagues used a modified version of the 6MWT to test 40 patients with MS and 20 healthy controls. The modified version differed from the regular 6MWT in that subjects were told to walk as quickly as possible, were not told that they could rest during the test, and were not offered encouragement during the test.

Among the patients with MS, total 6MWT distance decreased with increasing disability, the 6MWT showed excellent intra-rated and inter-rated reliability, and subjective measures of ambulation and fatigue were more closely correlated with 6MWT results than with EDSS results. The researchers concluded that the modified 6MWT “is a feasible, reproducible, and reliable measure in MS.”

However, only six of that study’s 40 participants with MS had severe disease. “So while this work was valuable, one of its limitations was in determining the feasibility of the 6MWT in a more advanced, ambulatory-impaired MS population,” Dr. Goldman noted.

A 41% Increase in Precision
In the current study, Dr. Goldman and colleagues investigated the modified 6MWT’s utility in a population of 96 participants with confirmed MS, ensuring that their cohort included a high percentage of patients with severe disease. Of the study participants, 30 had mild MS (EDSS scores of 2 to 3.5), 29 had moderate MS (scores of 4 to 5.5), and 37 had severe MS (scores of 6 to 6.5). The subjects were evaluated with the 6MWT, the T25FW, and the MSWS-12.

A majority of participants were female, and an overwhelming majority were white. Their mean duration of MS was 11.8 years, 82% of them had relapsing-remitting MS, and 80% were receiving disease-modifying therapy. All of the subjects walked continuously for the full six minutes of the 6MWT.

Their total distance on the 6MWT was inversely correlated with their EDSS status, the researchers found. Among the total cohort, results on the 6MWT and the T25FW were strongly and significantly correlated, noted Dr. Goldman.

However, the 6MWT was 41% more precise than the T25FW in identifying EDSS subgroups. Although the 6MWT was able to distinguish between all of these subgroups, the T25FW was unable to distinguish between the mild and moderate subgroups.

Both the 6MWT and the T25FW were correlated with the overall cohort’s self-reports on the MSWS-12, but not with those of the mild or severe subgroups. These disparities were driven by the MSWS-12 questions about patients’ use of walking support, according to Dr. Goldman.

“When you use walking assistance or a device, it pushes you into an MSWS-12 subset, but your performance on actual walking may not be correlated to that,” she said. “Patients can walk very poorly when unassisted, but then you give them a rollator or walker, and their walking performance actually improves, because you have compensated for some of the balance issues, instability, and fear of falling that was affecting their speed and movement. So while their 6MWT score may improve, their MSWS-12 score would worsen.”

The Best Clinical Tool?
These results confirm that the 6MWT is feasible, tolerated, and more precise than the T25FW in patients with MS, including those with severe disease. However, she emphasized, more research is necessary, according to Dr. Goldman.

“We need to learn more about the 6MWT’s responsiveness,” she said. “We want to understand its longitudinal behavior over time relative to other outcome measures and to clinically meaningful change. Finally, we need additional studies to explore the performance of the MSMS-12 at the two bookends of this ambulatory population.”

In response to the concern that the 6MWT is more difficult to perform than the T25FW in a clinical setting, Dr. Goldman replied, “I think there are two different questions that have to be addressed—how we determine efficacy in clinical trials in the research arena and how we manage patients in our practices.

“Using the 6MWT on every patient who comes into the office is a very difficult thing to do—I am the 6MWT champion, and I find it difficult to do in my clinical practice,” she commented.

“But when we consider that we may be discarding drugs with a therapeutic impact that we can’t detect using our current measures, it seems that a little bit of burden may go a long way,” Dr. Goldman continued. “What I’m getting at is not necessarily, ‘How do we manage a patient day-to-day in our clinical practice?’ It’s, ‘What’s the best way to detect if the therapies are effective?’ And I think the tools that we should pick are going to vary depending on the task at hand.”

MONTREAL—A modified version of the Six-Minute Walk Test (6MWT) may measure walking disability in patients with multiple sclerosis (MS) more precisely than the tests currently used for this purpose, according to research presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“The 6MWT is feasible and tolerated in subjects with MS, including those in the upper Expanded Disability Status Scale (EDSS) range of 4.0 to 6.5,” said Myla Goldman, MD, of the Department of Neurology at the University of Virginia in Charlottesville. “The 6MWT and the Timed 25-Foot Walk (T25FW) are well-correlated variables, but overall, the 6MWT appears to have increased precision in identifying EDSS subgroups.”

Dr. Goldman and colleagues came to these conclusions by testing the 6MWT, which historically has been used in patients with respiratory or cardiac disease, in a cohort of 96 patients with MS.

In addition to showing greater precision than the T25FW, the 6MWT correlated fairly well with the Multiple Sclerosis Walking Scale-12 (MSWS-12), a subjective measure of MS walking disability.

The Search for an Alternative Measure
The currently accepted measures of MS walking disability all have important limitations, according to Dr. Goldman. Some patients with mild MS may have walking difficulties below the threshold detectible by the T25FW (the ambulatory component of the Multiple Sclerosis Functional Composite) or the EDSS ambulatory component, she said, adding that the EDSS’s compression of data into ordinal variables limits its sensitivity. Because the MSWS-12 depends on subjective reports from patients, she added, it needs to be considered in conjunction with more objective measures.

With these limitations in mind, the researchers turned to the 6MWT, which determines walking capacity by having subjects walk as far as they can in six minutes. The test is administered on an indoor walking course of at least 30 meters, and persons are asked to pivot and continue to walk whenever they reach an end of the course. The primary outcome is total distance walked, but other assessed outcomes can include subjects’ heart rate, dyspnea, fatigue, and oxygen saturation before and after the test; stopping or pausing during the test; and symptoms of angina, dizziness, or pain at the end of the test.

In a 2008 study, Dr. Goldman and colleagues used a modified version of the 6MWT to test 40 patients with MS and 20 healthy controls. The modified version differed from the regular 6MWT in that subjects were told to walk as quickly as possible, were not told that they could rest during the test, and were not offered encouragement during the test.

Among the patients with MS, total 6MWT distance decreased with increasing disability, the 6MWT showed excellent intra-rated and inter-rated reliability, and subjective measures of ambulation and fatigue were more closely correlated with 6MWT results than with EDSS results. The researchers concluded that the modified 6MWT “is a feasible, reproducible, and reliable measure in MS.”

However, only six of that study’s 40 participants with MS had severe disease. “So while this work was valuable, one of its limitations was in determining the feasibility of the 6MWT in a more advanced, ambulatory-impaired MS population,” Dr. Goldman noted.

A 41% Increase in Precision
In the current study, Dr. Goldman and colleagues investigated the modified 6MWT’s utility in a population of 96 participants with confirmed MS, ensuring that their cohort included a high percentage of patients with severe disease. Of the study participants, 30 had mild MS (EDSS scores of 2 to 3.5), 29 had moderate MS (scores of 4 to 5.5), and 37 had severe MS (scores of 6 to 6.5). The subjects were evaluated with the 6MWT, the T25FW, and the MSWS-12.

A majority of participants were female, and an overwhelming majority were white. Their mean duration of MS was 11.8 years, 82% of them had relapsing-remitting MS, and 80% were receiving disease-modifying therapy. All of the subjects walked continuously for the full six minutes of the 6MWT.

Their total distance on the 6MWT was inversely correlated with their EDSS status, the researchers found. Among the total cohort, results on the 6MWT and the T25FW were strongly and significantly correlated, noted Dr. Goldman.

However, the 6MWT was 41% more precise than the T25FW in identifying EDSS subgroups. Although the 6MWT was able to distinguish between all of these subgroups, the T25FW was unable to distinguish between the mild and moderate subgroups.

Both the 6MWT and the T25FW were correlated with the overall cohort’s self-reports on the MSWS-12, but not with those of the mild or severe subgroups. These disparities were driven by the MSWS-12 questions about patients’ use of walking support, according to Dr. Goldman.

“When you use walking assistance or a device, it pushes you into an MSWS-12 subset, but your performance on actual walking may not be correlated to that,” she said. “Patients can walk very poorly when unassisted, but then you give them a rollator or walker, and their walking performance actually improves, because you have compensated for some of the balance issues, instability, and fear of falling that was affecting their speed and movement. So while their 6MWT score may improve, their MSWS-12 score would worsen.”

The Best Clinical Tool?
These results confirm that the 6MWT is feasible, tolerated, and more precise than the T25FW in patients with MS, including those with severe disease. However, she emphasized, more research is necessary, according to Dr. Goldman.

“We need to learn more about the 6MWT’s responsiveness,” she said. “We want to understand its longitudinal behavior over time relative to other outcome measures and to clinically meaningful change. Finally, we need additional studies to explore the performance of the MSMS-12 at the two bookends of this ambulatory population.”

In response to the concern that the 6MWT is more difficult to perform than the T25FW in a clinical setting, Dr. Goldman replied, “I think there are two different questions that have to be addressed—how we determine efficacy in clinical trials in the research arena and how we manage patients in our practices.

“Using the 6MWT on every patient who comes into the office is a very difficult thing to do—I am the 6MWT champion, and I find it difficult to do in my clinical practice,” she commented.

“But when we consider that we may be discarding drugs with a therapeutic impact that we can’t detect using our current measures, it seems that a little bit of burden may go a long way,” Dr. Goldman continued. “What I’m getting at is not necessarily, ‘How do we manage a patient day-to-day in our clinical practice?’ It’s, ‘What’s the best way to detect if the therapies are effective?’ And I think the tools that we should pick are going to vary depending on the task at hand.”

MONTREAL—A modified version of the Six-Minute Walk Test (6MWT) may measure walking disability in patients with multiple sclerosis (MS) more precisely than the tests currently used for this purpose, according to research presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“The 6MWT is feasible and tolerated in subjects with MS, including those in the upper Expanded Disability Status Scale (EDSS) range of 4.0 to 6.5,” said Myla Goldman, MD, of the Department of Neurology at the University of Virginia in Charlottesville. “The 6MWT and the Timed 25-Foot Walk (T25FW) are well-correlated variables, but overall, the 6MWT appears to have increased precision in identifying EDSS subgroups.”

Dr. Goldman and colleagues came to these conclusions by testing the 6MWT, which historically has been used in patients with respiratory or cardiac disease, in a cohort of 96 patients with MS.

In addition to showing greater precision than the T25FW, the 6MWT correlated fairly well with the Multiple Sclerosis Walking Scale-12 (MSWS-12), a subjective measure of MS walking disability.

The Search for an Alternative Measure
The currently accepted measures of MS walking disability all have important limitations, according to Dr. Goldman. Some patients with mild MS may have walking difficulties below the threshold detectible by the T25FW (the ambulatory component of the Multiple Sclerosis Functional Composite) or the EDSS ambulatory component, she said, adding that the EDSS’s compression of data into ordinal variables limits its sensitivity. Because the MSWS-12 depends on subjective reports from patients, she added, it needs to be considered in conjunction with more objective measures.

With these limitations in mind, the researchers turned to the 6MWT, which determines walking capacity by having subjects walk as far as they can in six minutes. The test is administered on an indoor walking course of at least 30 meters, and persons are asked to pivot and continue to walk whenever they reach an end of the course. The primary outcome is total distance walked, but other assessed outcomes can include subjects’ heart rate, dyspnea, fatigue, and oxygen saturation before and after the test; stopping or pausing during the test; and symptoms of angina, dizziness, or pain at the end of the test.

In a 2008 study, Dr. Goldman and colleagues used a modified version of the 6MWT to test 40 patients with MS and 20 healthy controls. The modified version differed from the regular 6MWT in that subjects were told to walk as quickly as possible, were not told that they could rest during the test, and were not offered encouragement during the test.

Among the patients with MS, total 6MWT distance decreased with increasing disability, the 6MWT showed excellent intra-rated and inter-rated reliability, and subjective measures of ambulation and fatigue were more closely correlated with 6MWT results than with EDSS results. The researchers concluded that the modified 6MWT “is a feasible, reproducible, and reliable measure in MS.”

However, only six of that study’s 40 participants with MS had severe disease. “So while this work was valuable, one of its limitations was in determining the feasibility of the 6MWT in a more advanced, ambulatory-impaired MS population,” Dr. Goldman noted.

A 41% Increase in Precision
In the current study, Dr. Goldman and colleagues investigated the modified 6MWT’s utility in a population of 96 participants with confirmed MS, ensuring that their cohort included a high percentage of patients with severe disease. Of the study participants, 30 had mild MS (EDSS scores of 2 to 3.5), 29 had moderate MS (scores of 4 to 5.5), and 37 had severe MS (scores of 6 to 6.5). The subjects were evaluated with the 6MWT, the T25FW, and the MSWS-12.

A majority of participants were female, and an overwhelming majority were white. Their mean duration of MS was 11.8 years, 82% of them had relapsing-remitting MS, and 80% were receiving disease-modifying therapy. All of the subjects walked continuously for the full six minutes of the 6MWT.

Their total distance on the 6MWT was inversely correlated with their EDSS status, the researchers found. Among the total cohort, results on the 6MWT and the T25FW were strongly and significantly correlated, noted Dr. Goldman.

However, the 6MWT was 41% more precise than the T25FW in identifying EDSS subgroups. Although the 6MWT was able to distinguish between all of these subgroups, the T25FW was unable to distinguish between the mild and moderate subgroups.

Both the 6MWT and the T25FW were correlated with the overall cohort’s self-reports on the MSWS-12, but not with those of the mild or severe subgroups. These disparities were driven by the MSWS-12 questions about patients’ use of walking support, according to Dr. Goldman.

“When you use walking assistance or a device, it pushes you into an MSWS-12 subset, but your performance on actual walking may not be correlated to that,” she said. “Patients can walk very poorly when unassisted, but then you give them a rollator or walker, and their walking performance actually improves, because you have compensated for some of the balance issues, instability, and fear of falling that was affecting their speed and movement. So while their 6MWT score may improve, their MSWS-12 score would worsen.”

The Best Clinical Tool?
These results confirm that the 6MWT is feasible, tolerated, and more precise than the T25FW in patients with MS, including those with severe disease. However, she emphasized, more research is necessary, according to Dr. Goldman.

“We need to learn more about the 6MWT’s responsiveness,” she said. “We want to understand its longitudinal behavior over time relative to other outcome measures and to clinically meaningful change. Finally, we need additional studies to explore the performance of the MSMS-12 at the two bookends of this ambulatory population.”

In response to the concern that the 6MWT is more difficult to perform than the T25FW in a clinical setting, Dr. Goldman replied, “I think there are two different questions that have to be addressed—how we determine efficacy in clinical trials in the research arena and how we manage patients in our practices.

“Using the 6MWT on every patient who comes into the office is a very difficult thing to do—I am the 6MWT champion, and I find it difficult to do in my clinical practice,” she commented.

“But when we consider that we may be discarding drugs with a therapeutic impact that we can’t detect using our current measures, it seems that a little bit of burden may go a long way,” Dr. Goldman continued. “What I’m getting at is not necessarily, ‘How do we manage a patient day-to-day in our clinical practice?’ It’s, ‘What’s the best way to detect if the therapies are effective?’ And I think the tools that we should pick are going to vary depending on the task at hand.”

New Risk Factors for Alzheimer’s Disease?
Vision and hearing deficits, poorly fitting dentures, and increased serum proinflammatory cytokines all may be risk factors for Alzheimer’s disease, according to three studies published in the July 12 online issue of Neurology.
Alzheimer’s disease and dementia risk were associated with health deficits that are usually seen in the elderly but were not previously known to predict dementia, according to a study by Xiaowei Song, PhD, of Dalhousie University, Halifax, Canada, and colleagues.
The investigators created an index combining 19 such deficits—including problems with vision, hearing, denture fit, chest or skin, stomach or bladder, sinuses, broken bones, and feet or ankles—and applied it to 7,239 participants who were age 65 or older and free of dementia at baseline. After adjustment for age, sex, education, and baseline cognition, participants’ index scores were significantly associated with Alzheimer’s disease and dementia of all types at five and 10 years. In addition, their risk of dementia increased by 3.2% with each deficit included in the index.
Both lower and higher levels of hemoglobin were associated with Alzheimer’s disease and cognitive decline in a study by Raj C. Shah, MD, of Rush University Medical Center in Chicago, and colleagues. They gave annual cognitive assessments and clinical evaluations for Alzheimer’s disease to 881 community-dwelling, elderly participants for a mean of 3.3 years.
With adjustment for age, sex, and education, higher and lower levels of hemoglobin were associated with Alzheimer’s disease risk, with a hazard ratio of 1.06 for the quadratic of hemoglobin. Participants who had anemia or clinically high hemoglobin had a 60% increased risk of Alzheimer’s disease dementia, compared with participants who had clinically normal hemoglobin.
Increased serum proinflammatory cytokines predicted such “sickness behaviors” as increased anxiety, depression, and apathy in patients with Alzheimer’s disease, according to a study by Clive Holmes, PhD, of the University of Southampton, Southampton, UK, and colleagues. The investigators took blood samples from and performed cognitive assessments on 300 patients with mild to severe Alzheimer’s disease at baseline and two, four, and six months. Increased levels of serum tumor necrosis factor and IL-6 at baseline were associated with an approximately twofold increased frequency of neuropsychiatric symptoms characteristic of sickness behavior, independent of a history of delirium, at six months.
Despite these findings, “much uncertainty remains” about the value of nontraditional Alzheimer’s disease risk factors, emphasized Jean François Dartigues, MD, PhD, and Catherine Féart, PhD, both of the University of Victor Segalen of Bordeaux, Bordeaux, France, in an accompanying editorial. They suggested that “the studied factors could be a nonspecific consequence of aging phenomenon” and that health-related behaviors, nutritional factors, physical activities, or leisure activities could have affected the studies’ results.
Nevertheless, they added, the studies “suggest a new vision of preventive or curative treatments which, instead of targeting specific etiologic mechanisms, would aim at improving general health. Perhaps increasing adaptation to age-related changes would reduce the risk of Alzheimer’s disease dementia or its impact on the patient, caregivers, and society.”
Holmes C, Cunningham C, Zotova E, et al. Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology. 2011;77(3):212-218.
Shah RC, Buchman AS, Wilson RS, et al. Hemoglobin level in older persons and incident Alzheimer disease: prospective cohort analysis. Neurology. 2011;77(3):219-226.
Song X, Mitnitski A, Rockwood K. Nontraditional risk factors combine to predict Alzheimer disease and dementia. Neurology. 2011;77(3):227-234.
Dartigues JF, Féart C. Risk factors for Alzheimer disease: aging beyond age? Neurology. 2011;77(3):206-207.

Reducing Tonic-Clonic Seizures Can Minimize Risk of SUDEP
Clinicians can minimize the risk of sudden unexpected death in epilepsy (SUDEP) through such measures as reducing tonic-clonic seizures, choosing drugs carefully, changing treatments gradually, acting on ictal warning signs, and supervising and counseling patients, according to a seminar published online July 6 in Lancet. The seminar, by Simon Shorvon, FRCP, of the UCL Institute of Neurology in London, and Torbjorn Tomson, MD, of the Karolinska Institute in Stockholm, reviewed current research on and provided advice about minimizing SUDEP risk.
Almost all studies indicate that this risk is high in patients with a high number of tonic-clonic seizures, the authors noted. They suggested reducing these seizures through optimum treatment, good drug compliance, and advice on such lifestyle choices as alcohol intake and sleep. Ictal warning signs for tonic-clonic seizures include prolonged seizures that are associated with marked cyanosis, severe bradycardia or apnea, and postictal EEG suppression; complex partial seizures with marked atonia; and seizures in patients with pre-existing cardiac or respiratory impairment.
Patients who experience tonic-clonic seizures require supervision, the authors noted. They recommended attending to these patients continuously until the full restoration of consciousness, contacting emergency services for high-risk seizures, and supervising high-risk patients at night through attendance and use of alarms.
Clinicians should be cautious in using antiepileptic drugs (AEDs) with potential cardiorespiratory adverse effects, according to the researchers. When clinicians switch AEDs, they should introduce the new drug before withdrawing the old one and provide patients with “access to immediate advice in the event of worsening seizures,” the investigators stated.
Although some clinicians believe that informing all patients with epilepsy about the risk of SUDEP will cause unnecessary stress and anxiety, the authors recommended informing most patients about the risk to facilitate its minimization. However, they further suggested putting the risk in perspective—for example, by pointing out that, on an annual basis, it is similar to that of dying in a motor vehicle accident.
SUDEP probably has several mechanisms, and “most research has focused on seizure-related respiratory depression, cardiac arrhythmia, cerebral depression, and autonomic dysfunction,” the authors noted. Along with tonic-clonic seizures, risk factors for the event include male sex, long-duration epilepsy, and antiepileptic polytherapy.
Shorvon S, Tomson T. Sudden unexpected death in epilepsy. Lancet. 2011 Jul 5; [Epub ahead of print].

How Cost-Effective Are Disease-Modifying Therapies in MS?
Disease-modifying therapies (DMTs) for relapsing-remitting or secondary progressive multiple sclerosis (MS) do not appear to be cost-effective in the United States, according to findings published online July 20 by Neurology.
Katia Noyes, PhD, MPH, of the University of Rochester, New York, and colleagues calculated the cost-effectiveness of four DMTs in a  nationally representative cohort of 1,121 patients with MS. The investigators generated 10-year disease progression paths for this cohort; looked at data on drug effectiveness, patient health preferences, health care use, lost productivity, and medical costs; measured health gains in quality-adjusted life-years (QALYs) and relapse-free years; and calculated incremental cost-effectiveness ratios (ICERs). The DMTs studied were glatiramer acetate, intramuscular interferon beta-1a, subcutaneous interferon beta-1a, and interferon beta-1b.
DMT therapy for 10 years resulted in modest QALY gains (0.082 for glatiramer acetate and 0.126 to 0.192 for the interferons), compared with basic supportive therapy. In addition, DMT therapy resulted in more relapse-free years throughout the course of a decade; patients on basic therapy averaged 5.051 relapse-free years, compared with 5.879 relapse-free years for glatiramer acetate and 5.620 to 6.074 relapse-free years for the interferons.
However, the ICERs of all four DMTs far exceeded $800,000 per QALY gained. The interferons had similar ICERs, at $901,319/QALY for intramuscular interferon beta-1a, $1,487,306/QALY for subcutaneous interferon beta-1a, and $1,123,162/QALY for interferon beta-1b. The ICER for glatiramer acetate was significantly higher, at $2,178,555/QALY. “While there is no formal cost-effectiveness threshold in the US, these estimates are an order of magnitude greater than the cost-effectiveness of many commonly accepted therapies for chronic illness,” the researchers commented.
The researchers added that cutting DMT costs by two-thirds would make the therapies’ cost-effectiveness comparable to that of other accepted interventions, however. In addition, the investigators noted that starting DMT earlier was associated with a more favorable ICER, compared with initiating treatment at any disease state, and that early treatment “may defer the substantial costs associated with late-stage MS and disability.”
Noyes K, Bajorska A, Chappel A, et al. Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study. Neurology. 2011 Jul 20; [Epub ahead of print]. 

New Risk Factors for Alzheimer’s Disease?
Vision and hearing deficits, poorly fitting dentures, and increased serum proinflammatory cytokines all may be risk factors for Alzheimer’s disease, according to three studies published in the July 12 online issue of Neurology.
Alzheimer’s disease and dementia risk were associated with health deficits that are usually seen in the elderly but were not previously known to predict dementia, according to a study by Xiaowei Song, PhD, of Dalhousie University, Halifax, Canada, and colleagues.
The investigators created an index combining 19 such deficits—including problems with vision, hearing, denture fit, chest or skin, stomach or bladder, sinuses, broken bones, and feet or ankles—and applied it to 7,239 participants who were age 65 or older and free of dementia at baseline. After adjustment for age, sex, education, and baseline cognition, participants’ index scores were significantly associated with Alzheimer’s disease and dementia of all types at five and 10 years. In addition, their risk of dementia increased by 3.2% with each deficit included in the index.
Both lower and higher levels of hemoglobin were associated with Alzheimer’s disease and cognitive decline in a study by Raj C. Shah, MD, of Rush University Medical Center in Chicago, and colleagues. They gave annual cognitive assessments and clinical evaluations for Alzheimer’s disease to 881 community-dwelling, elderly participants for a mean of 3.3 years.
With adjustment for age, sex, and education, higher and lower levels of hemoglobin were associated with Alzheimer’s disease risk, with a hazard ratio of 1.06 for the quadratic of hemoglobin. Participants who had anemia or clinically high hemoglobin had a 60% increased risk of Alzheimer’s disease dementia, compared with participants who had clinically normal hemoglobin.
Increased serum proinflammatory cytokines predicted such “sickness behaviors” as increased anxiety, depression, and apathy in patients with Alzheimer’s disease, according to a study by Clive Holmes, PhD, of the University of Southampton, Southampton, UK, and colleagues. The investigators took blood samples from and performed cognitive assessments on 300 patients with mild to severe Alzheimer’s disease at baseline and two, four, and six months. Increased levels of serum tumor necrosis factor and IL-6 at baseline were associated with an approximately twofold increased frequency of neuropsychiatric symptoms characteristic of sickness behavior, independent of a history of delirium, at six months.
Despite these findings, “much uncertainty remains” about the value of nontraditional Alzheimer’s disease risk factors, emphasized Jean François Dartigues, MD, PhD, and Catherine Féart, PhD, both of the University of Victor Segalen of Bordeaux, Bordeaux, France, in an accompanying editorial. They suggested that “the studied factors could be a nonspecific consequence of aging phenomenon” and that health-related behaviors, nutritional factors, physical activities, or leisure activities could have affected the studies’ results.
Nevertheless, they added, the studies “suggest a new vision of preventive or curative treatments which, instead of targeting specific etiologic mechanisms, would aim at improving general health. Perhaps increasing adaptation to age-related changes would reduce the risk of Alzheimer’s disease dementia or its impact on the patient, caregivers, and society.”
Holmes C, Cunningham C, Zotova E, et al. Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology. 2011;77(3):212-218.
Shah RC, Buchman AS, Wilson RS, et al. Hemoglobin level in older persons and incident Alzheimer disease: prospective cohort analysis. Neurology. 2011;77(3):219-226.
Song X, Mitnitski A, Rockwood K. Nontraditional risk factors combine to predict Alzheimer disease and dementia. Neurology. 2011;77(3):227-234.
Dartigues JF, Féart C. Risk factors for Alzheimer disease: aging beyond age? Neurology. 2011;77(3):206-207.

Reducing Tonic-Clonic Seizures Can Minimize Risk of SUDEP
Clinicians can minimize the risk of sudden unexpected death in epilepsy (SUDEP) through such measures as reducing tonic-clonic seizures, choosing drugs carefully, changing treatments gradually, acting on ictal warning signs, and supervising and counseling patients, according to a seminar published online July 6 in Lancet. The seminar, by Simon Shorvon, FRCP, of the UCL Institute of Neurology in London, and Torbjorn Tomson, MD, of the Karolinska Institute in Stockholm, reviewed current research on and provided advice about minimizing SUDEP risk.
Almost all studies indicate that this risk is high in patients with a high number of tonic-clonic seizures, the authors noted. They suggested reducing these seizures through optimum treatment, good drug compliance, and advice on such lifestyle choices as alcohol intake and sleep. Ictal warning signs for tonic-clonic seizures include prolonged seizures that are associated with marked cyanosis, severe bradycardia or apnea, and postictal EEG suppression; complex partial seizures with marked atonia; and seizures in patients with pre-existing cardiac or respiratory impairment.
Patients who experience tonic-clonic seizures require supervision, the authors noted. They recommended attending to these patients continuously until the full restoration of consciousness, contacting emergency services for high-risk seizures, and supervising high-risk patients at night through attendance and use of alarms.
Clinicians should be cautious in using antiepileptic drugs (AEDs) with potential cardiorespiratory adverse effects, according to the researchers. When clinicians switch AEDs, they should introduce the new drug before withdrawing the old one and provide patients with “access to immediate advice in the event of worsening seizures,” the investigators stated.
Although some clinicians believe that informing all patients with epilepsy about the risk of SUDEP will cause unnecessary stress and anxiety, the authors recommended informing most patients about the risk to facilitate its minimization. However, they further suggested putting the risk in perspective—for example, by pointing out that, on an annual basis, it is similar to that of dying in a motor vehicle accident.
SUDEP probably has several mechanisms, and “most research has focused on seizure-related respiratory depression, cardiac arrhythmia, cerebral depression, and autonomic dysfunction,” the authors noted. Along with tonic-clonic seizures, risk factors for the event include male sex, long-duration epilepsy, and antiepileptic polytherapy.
Shorvon S, Tomson T. Sudden unexpected death in epilepsy. Lancet. 2011 Jul 5; [Epub ahead of print].

How Cost-Effective Are Disease-Modifying Therapies in MS?
Disease-modifying therapies (DMTs) for relapsing-remitting or secondary progressive multiple sclerosis (MS) do not appear to be cost-effective in the United States, according to findings published online July 20 by Neurology.
Katia Noyes, PhD, MPH, of the University of Rochester, New York, and colleagues calculated the cost-effectiveness of four DMTs in a  nationally representative cohort of 1,121 patients with MS. The investigators generated 10-year disease progression paths for this cohort; looked at data on drug effectiveness, patient health preferences, health care use, lost productivity, and medical costs; measured health gains in quality-adjusted life-years (QALYs) and relapse-free years; and calculated incremental cost-effectiveness ratios (ICERs). The DMTs studied were glatiramer acetate, intramuscular interferon beta-1a, subcutaneous interferon beta-1a, and interferon beta-1b.
DMT therapy for 10 years resulted in modest QALY gains (0.082 for glatiramer acetate and 0.126 to 0.192 for the interferons), compared with basic supportive therapy. In addition, DMT therapy resulted in more relapse-free years throughout the course of a decade; patients on basic therapy averaged 5.051 relapse-free years, compared with 5.879 relapse-free years for glatiramer acetate and 5.620 to 6.074 relapse-free years for the interferons.
However, the ICERs of all four DMTs far exceeded $800,000 per QALY gained. The interferons had similar ICERs, at $901,319/QALY for intramuscular interferon beta-1a, $1,487,306/QALY for subcutaneous interferon beta-1a, and $1,123,162/QALY for interferon beta-1b. The ICER for glatiramer acetate was significantly higher, at $2,178,555/QALY. “While there is no formal cost-effectiveness threshold in the US, these estimates are an order of magnitude greater than the cost-effectiveness of many commonly accepted therapies for chronic illness,” the researchers commented.
The researchers added that cutting DMT costs by two-thirds would make the therapies’ cost-effectiveness comparable to that of other accepted interventions, however. In addition, the investigators noted that starting DMT earlier was associated with a more favorable ICER, compared with initiating treatment at any disease state, and that early treatment “may defer the substantial costs associated with late-stage MS and disability.”
Noyes K, Bajorska A, Chappel A, et al. Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study. Neurology. 2011 Jul 20; [Epub ahead of print]. 

New Risk Factors for Alzheimer’s Disease?
Vision and hearing deficits, poorly fitting dentures, and increased serum proinflammatory cytokines all may be risk factors for Alzheimer’s disease, according to three studies published in the July 12 online issue of Neurology.
Alzheimer’s disease and dementia risk were associated with health deficits that are usually seen in the elderly but were not previously known to predict dementia, according to a study by Xiaowei Song, PhD, of Dalhousie University, Halifax, Canada, and colleagues.
The investigators created an index combining 19 such deficits—including problems with vision, hearing, denture fit, chest or skin, stomach or bladder, sinuses, broken bones, and feet or ankles—and applied it to 7,239 participants who were age 65 or older and free of dementia at baseline. After adjustment for age, sex, education, and baseline cognition, participants’ index scores were significantly associated with Alzheimer’s disease and dementia of all types at five and 10 years. In addition, their risk of dementia increased by 3.2% with each deficit included in the index.
Both lower and higher levels of hemoglobin were associated with Alzheimer’s disease and cognitive decline in a study by Raj C. Shah, MD, of Rush University Medical Center in Chicago, and colleagues. They gave annual cognitive assessments and clinical evaluations for Alzheimer’s disease to 881 community-dwelling, elderly participants for a mean of 3.3 years.
With adjustment for age, sex, and education, higher and lower levels of hemoglobin were associated with Alzheimer’s disease risk, with a hazard ratio of 1.06 for the quadratic of hemoglobin. Participants who had anemia or clinically high hemoglobin had a 60% increased risk of Alzheimer’s disease dementia, compared with participants who had clinically normal hemoglobin.
Increased serum proinflammatory cytokines predicted such “sickness behaviors” as increased anxiety, depression, and apathy in patients with Alzheimer’s disease, according to a study by Clive Holmes, PhD, of the University of Southampton, Southampton, UK, and colleagues. The investigators took blood samples from and performed cognitive assessments on 300 patients with mild to severe Alzheimer’s disease at baseline and two, four, and six months. Increased levels of serum tumor necrosis factor and IL-6 at baseline were associated with an approximately twofold increased frequency of neuropsychiatric symptoms characteristic of sickness behavior, independent of a history of delirium, at six months.
Despite these findings, “much uncertainty remains” about the value of nontraditional Alzheimer’s disease risk factors, emphasized Jean François Dartigues, MD, PhD, and Catherine Féart, PhD, both of the University of Victor Segalen of Bordeaux, Bordeaux, France, in an accompanying editorial. They suggested that “the studied factors could be a nonspecific consequence of aging phenomenon” and that health-related behaviors, nutritional factors, physical activities, or leisure activities could have affected the studies’ results.
Nevertheless, they added, the studies “suggest a new vision of preventive or curative treatments which, instead of targeting specific etiologic mechanisms, would aim at improving general health. Perhaps increasing adaptation to age-related changes would reduce the risk of Alzheimer’s disease dementia or its impact on the patient, caregivers, and society.”
Holmes C, Cunningham C, Zotova E, et al. Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology. 2011;77(3):212-218.
Shah RC, Buchman AS, Wilson RS, et al. Hemoglobin level in older persons and incident Alzheimer disease: prospective cohort analysis. Neurology. 2011;77(3):219-226.
Song X, Mitnitski A, Rockwood K. Nontraditional risk factors combine to predict Alzheimer disease and dementia. Neurology. 2011;77(3):227-234.
Dartigues JF, Féart C. Risk factors for Alzheimer disease: aging beyond age? Neurology. 2011;77(3):206-207.

Reducing Tonic-Clonic Seizures Can Minimize Risk of SUDEP
Clinicians can minimize the risk of sudden unexpected death in epilepsy (SUDEP) through such measures as reducing tonic-clonic seizures, choosing drugs carefully, changing treatments gradually, acting on ictal warning signs, and supervising and counseling patients, according to a seminar published online July 6 in Lancet. The seminar, by Simon Shorvon, FRCP, of the UCL Institute of Neurology in London, and Torbjorn Tomson, MD, of the Karolinska Institute in Stockholm, reviewed current research on and provided advice about minimizing SUDEP risk.
Almost all studies indicate that this risk is high in patients with a high number of tonic-clonic seizures, the authors noted. They suggested reducing these seizures through optimum treatment, good drug compliance, and advice on such lifestyle choices as alcohol intake and sleep. Ictal warning signs for tonic-clonic seizures include prolonged seizures that are associated with marked cyanosis, severe bradycardia or apnea, and postictal EEG suppression; complex partial seizures with marked atonia; and seizures in patients with pre-existing cardiac or respiratory impairment.
Patients who experience tonic-clonic seizures require supervision, the authors noted. They recommended attending to these patients continuously until the full restoration of consciousness, contacting emergency services for high-risk seizures, and supervising high-risk patients at night through attendance and use of alarms.
Clinicians should be cautious in using antiepileptic drugs (AEDs) with potential cardiorespiratory adverse effects, according to the researchers. When clinicians switch AEDs, they should introduce the new drug before withdrawing the old one and provide patients with “access to immediate advice in the event of worsening seizures,” the investigators stated.
Although some clinicians believe that informing all patients with epilepsy about the risk of SUDEP will cause unnecessary stress and anxiety, the authors recommended informing most patients about the risk to facilitate its minimization. However, they further suggested putting the risk in perspective—for example, by pointing out that, on an annual basis, it is similar to that of dying in a motor vehicle accident.
SUDEP probably has several mechanisms, and “most research has focused on seizure-related respiratory depression, cardiac arrhythmia, cerebral depression, and autonomic dysfunction,” the authors noted. Along with tonic-clonic seizures, risk factors for the event include male sex, long-duration epilepsy, and antiepileptic polytherapy.
Shorvon S, Tomson T. Sudden unexpected death in epilepsy. Lancet. 2011 Jul 5; [Epub ahead of print].

How Cost-Effective Are Disease-Modifying Therapies in MS?
Disease-modifying therapies (DMTs) for relapsing-remitting or secondary progressive multiple sclerosis (MS) do not appear to be cost-effective in the United States, according to findings published online July 20 by Neurology.
Katia Noyes, PhD, MPH, of the University of Rochester, New York, and colleagues calculated the cost-effectiveness of four DMTs in a  nationally representative cohort of 1,121 patients with MS. The investigators generated 10-year disease progression paths for this cohort; looked at data on drug effectiveness, patient health preferences, health care use, lost productivity, and medical costs; measured health gains in quality-adjusted life-years (QALYs) and relapse-free years; and calculated incremental cost-effectiveness ratios (ICERs). The DMTs studied were glatiramer acetate, intramuscular interferon beta-1a, subcutaneous interferon beta-1a, and interferon beta-1b.
DMT therapy for 10 years resulted in modest QALY gains (0.082 for glatiramer acetate and 0.126 to 0.192 for the interferons), compared with basic supportive therapy. In addition, DMT therapy resulted in more relapse-free years throughout the course of a decade; patients on basic therapy averaged 5.051 relapse-free years, compared with 5.879 relapse-free years for glatiramer acetate and 5.620 to 6.074 relapse-free years for the interferons.
However, the ICERs of all four DMTs far exceeded $800,000 per QALY gained. The interferons had similar ICERs, at $901,319/QALY for intramuscular interferon beta-1a, $1,487,306/QALY for subcutaneous interferon beta-1a, and $1,123,162/QALY for interferon beta-1b. The ICER for glatiramer acetate was significantly higher, at $2,178,555/QALY. “While there is no formal cost-effectiveness threshold in the US, these estimates are an order of magnitude greater than the cost-effectiveness of many commonly accepted therapies for chronic illness,” the researchers commented.
The researchers added that cutting DMT costs by two-thirds would make the therapies’ cost-effectiveness comparable to that of other accepted interventions, however. In addition, the investigators noted that starting DMT earlier was associated with a more favorable ICER, compared with initiating treatment at any disease state, and that early treatment “may defer the substantial costs associated with late-stage MS and disability.”
Noyes K, Bajorska A, Chappel A, et al. Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study. Neurology. 2011 Jul 20; [Epub ahead of print].