ICYMI Multiple Sclerosis

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]. 

More than 20% of patients with multiple sclerosis experience moderate to high trait anxiety—a psychological symptom whose role in the disease course has not been well-defined.

MONTREAL—State and trait anxiety are prevalent in patients with multiple sclerosis (MS), and that increased anxiety correlates strongly with lower mental quality of life and higher depression and fatigue, according to research that was presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
 “MS patients have an increased rate of psychological symptoms beyond those found in controls and even in other chronic diseases,” reported Line E. Hviid, a research assistant and study coordinator at the Brigham and Women’s Hospital at Harvard Medical School in Boston. “While depression in the MS population has been studied in great detail, there has been little study of anxiety in MS, despite evidence of a nearly equally high prevalence.”
Ms. Hviid and colleagues enrolled 303 patients (mean age, 47.2) with clinically isolated syndrome or MS and administered questionnaires regarding state and trait anxiety, quality of life and health status, fatigue, social support, and depression to examine the role of anxiety in MS disease course. The patients also completed cognitive screening tests and were annually evaluated using the Expanded Disability Status Scale (EDSS).
A Significant Number of Patients With MS Experience Anxiety
“Using the published normal ranges, 14.5% of our subjects reported moderate to high state anxiety and 21.9% reported moderate to high trait anxiety,” the investigators stated. “Only 3.0% of our subjects reported high state anxiety, and 9.3% reported high trait anxiety.”
The researchers found statistically significant correlations when comparing measures of state and trait anxiety and all patient-reported outcomes; the highest correlations were recorded between anxiety and depression, the mental health scale, and the mental components summary score.
The team of investigators also observed mild but statistically significant associations between anxiety and both EDSS scores and the number of recent attacks. “No significant differences were found due to cognitive functioning, disease duration, disease course, or treatment status,” they reported.
The weak but significant correlation observed between anxiety and physical functioning—as measured by EDSS scores—and the stronger relationship between anxiety and role-physical subscale of the health status questionnaire—which measures the impact of physical functioning on daily life—suggest that the impact of physical disability on anxiety may be more profound than the physical disability itself, according to the researchers.
Comorbidities of MS-Associated Anxiety
“A striking comorbidity was found between depression and anxiety,” the authors stated. Increased anxiety was also correlated with a lower mental quality of life, as well as with increased fatigue, depression, and lower levels of social support.
“Anxiety is an important feature of MS,” the researchers concluded. “These findings highlight the need for identification and treatment of patients with anxiety, particularly in patients who experience depression.”

More than 20% of patients with multiple sclerosis experience moderate to high trait anxiety—a psychological symptom whose role in the disease course has not been well-defined.

MONTREAL—State and trait anxiety are prevalent in patients with multiple sclerosis (MS), and that increased anxiety correlates strongly with lower mental quality of life and higher depression and fatigue, according to research that was presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
 “MS patients have an increased rate of psychological symptoms beyond those found in controls and even in other chronic diseases,” reported Line E. Hviid, a research assistant and study coordinator at the Brigham and Women’s Hospital at Harvard Medical School in Boston. “While depression in the MS population has been studied in great detail, there has been little study of anxiety in MS, despite evidence of a nearly equally high prevalence.”
Ms. Hviid and colleagues enrolled 303 patients (mean age, 47.2) with clinically isolated syndrome or MS and administered questionnaires regarding state and trait anxiety, quality of life and health status, fatigue, social support, and depression to examine the role of anxiety in MS disease course. The patients also completed cognitive screening tests and were annually evaluated using the Expanded Disability Status Scale (EDSS).
A Significant Number of Patients With MS Experience Anxiety
“Using the published normal ranges, 14.5% of our subjects reported moderate to high state anxiety and 21.9% reported moderate to high trait anxiety,” the investigators stated. “Only 3.0% of our subjects reported high state anxiety, and 9.3% reported high trait anxiety.”
The researchers found statistically significant correlations when comparing measures of state and trait anxiety and all patient-reported outcomes; the highest correlations were recorded between anxiety and depression, the mental health scale, and the mental components summary score.
The team of investigators also observed mild but statistically significant associations between anxiety and both EDSS scores and the number of recent attacks. “No significant differences were found due to cognitive functioning, disease duration, disease course, or treatment status,” they reported.
The weak but significant correlation observed between anxiety and physical functioning—as measured by EDSS scores—and the stronger relationship between anxiety and role-physical subscale of the health status questionnaire—which measures the impact of physical functioning on daily life—suggest that the impact of physical disability on anxiety may be more profound than the physical disability itself, according to the researchers.
Comorbidities of MS-Associated Anxiety
“A striking comorbidity was found between depression and anxiety,” the authors stated. Increased anxiety was also correlated with a lower mental quality of life, as well as with increased fatigue, depression, and lower levels of social support.
“Anxiety is an important feature of MS,” the researchers concluded. “These findings highlight the need for identification and treatment of patients with anxiety, particularly in patients who experience depression.”

More than 20% of patients with multiple sclerosis experience moderate to high trait anxiety—a psychological symptom whose role in the disease course has not been well-defined.

MONTREAL—State and trait anxiety are prevalent in patients with multiple sclerosis (MS), and that increased anxiety correlates strongly with lower mental quality of life and higher depression and fatigue, according to research that was presented at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
 “MS patients have an increased rate of psychological symptoms beyond those found in controls and even in other chronic diseases,” reported Line E. Hviid, a research assistant and study coordinator at the Brigham and Women’s Hospital at Harvard Medical School in Boston. “While depression in the MS population has been studied in great detail, there has been little study of anxiety in MS, despite evidence of a nearly equally high prevalence.”
Ms. Hviid and colleagues enrolled 303 patients (mean age, 47.2) with clinically isolated syndrome or MS and administered questionnaires regarding state and trait anxiety, quality of life and health status, fatigue, social support, and depression to examine the role of anxiety in MS disease course. The patients also completed cognitive screening tests and were annually evaluated using the Expanded Disability Status Scale (EDSS).
A Significant Number of Patients With MS Experience Anxiety
“Using the published normal ranges, 14.5% of our subjects reported moderate to high state anxiety and 21.9% reported moderate to high trait anxiety,” the investigators stated. “Only 3.0% of our subjects reported high state anxiety, and 9.3% reported high trait anxiety.”
The researchers found statistically significant correlations when comparing measures of state and trait anxiety and all patient-reported outcomes; the highest correlations were recorded between anxiety and depression, the mental health scale, and the mental components summary score.
The team of investigators also observed mild but statistically significant associations between anxiety and both EDSS scores and the number of recent attacks. “No significant differences were found due to cognitive functioning, disease duration, disease course, or treatment status,” they reported.
The weak but significant correlation observed between anxiety and physical functioning—as measured by EDSS scores—and the stronger relationship between anxiety and role-physical subscale of the health status questionnaire—which measures the impact of physical functioning on daily life—suggest that the impact of physical disability on anxiety may be more profound than the physical disability itself, according to the researchers.
Comorbidities of MS-Associated Anxiety
“A striking comorbidity was found between depression and anxiety,” the authors stated. Increased anxiety was also correlated with a lower mental quality of life, as well as with increased fatigue, depression, and lower levels of social support.
“Anxiety is an important feature of MS,” the researchers concluded. “These findings highlight the need for identification and treatment of patients with anxiety, particularly in patients who experience depression.”

Researchers identify clinical and MRI biomarkers that may help predict outcomes in patients with relapsing-remitting MS up to eight years after starting therapy.

HONOLULU—Higher brain volume at baseline and a greater medication possession ratio predicted improved long-term clinical outcomes among patients with relapsing-remitting multiple sclerosis (MS), according to research presented at the 63rd Annual Meeting of the American Academy of Neurology. In addition, a higher baseline Expanded Disability Status Scale (EDSS) score and a greater early increase in EDSS score predicted worse outcomes, researchers reported.

“Given the heterogeneous nature of MS, it is important to identify prognostic factors that may predict outcomes as long as eight years after starting therapy,” stated Anthony Traboulsee, MD, Assistant Professor of Neurology at the University of British Columbia in Vancouver, and colleagues. “Assessing baseline brain volume and closely monitoring early disability status may be important to consider in monitoring and treatment decisions.”

Long-Term Follow-Up After Treatment Initiation
Dr. Traboulsee’s group conducted the Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) long-term follow-up (LTFU) study to analyze early clinical and MRI variables as predictors of long-term outcomes in patients with relapsing-remitting MS. The PRISMS LTFU cohort was followed prospectively for as long as eight years, with a 68% patient return rate in the follow-up. “Assessment protocols remained consistent through the course of the PRISMS study, thereby providing one of the most complete datasets of its type available,” noted the investigators.

A total of 382 patients were included in the LTFU follow-up to PRISMS, in which 560 patients were originally randomized. Among the 382 patients in the LTFU, 136 patients had been initially randomized to receive interferon beta-1a 44 µg; 123 patients had received interferon beta-1a 22 µg subcutaneously three times per week; and 123 participants had received placebo. Post-hoc exploratory analyses were conducted on data collected from all LTFU patients and in the subcohort originally randomized to receive subcutaneous interferon beta-1a, who were referred to as early-start patients (n = 259).

Baseline variables and medication possession ratio, as an indicator of subcutaneous interferon beta-1a treatment exposure, were explored as candidate prognostic factors for outcomes measured from baseline to LTFU (for up to eight years). The authors also investigated indicators of early clinical and MRI activity from baseline to month 24 as candidate prognostic factors for outcomes measured from month 24 to LTFU.
Predicting Favorable and Unfavorable Outcomes in MS
The researchers found that age, duration of MS, baseline EDSS score, baseline log (T2 disease of burden), and baseline brain volume were univariate predictors for nearly all long-term outcomes as measured from baseline to LTFU among all patients and early-start patients. Medication possession ratio predicted most of the long-term outcomes measured from baseline to LTFU in all patients and was a predictor for several outcomes in early-start patients.

Early change in EDSS score up to two years was a univariate predictor for virtually all outcomes measured from month 24 to LTFU in all patients and early-start patients, according to the investigators. In addition, EDSS progression and the number of EDSS progressions during the first 24 months were  frequent predictors for clinical outcomes as measured from month 24 to LTFU in all patients and early-start patients.

“The early MRI activity indicators were significant univariate predictors of several long-term disability outcomes, but not as frequently as seen with early EDSS progression,” reported Dr. Traboulsee and colleagues. “Brain volumes at baseline continued to be a predictor in all final multivariate models for all long-term clinical outcomes in both patient groups measured from baseline to LTFU. EDSS score at baseline continued to be a predictor in most multivariate models in both patient groups measured from baseline to LTFU.”

In several multivariate models, medication possession ratio continued to be a predictor for all long-term clinical outcomes in the all-patient cohort measured from baseline to LTFU, noted the investigators. The change in EDSS score from baseline to month 24 continued to be a predictor in nearly all final multivariate models for long-term clinical outcomes in all patients, and in all final multivariate models for all long-term clinical outcomes in early-start patients. Also, short-term MRI activity was predictive of some of the long-term clinical outcomes.

“These data suggest that a good early clinical response—no EDSS progression—can be predictive of a favorable long-term outcome,” Dr. Traboulsee and colleagues concluded. “However, patients who show worrisome signs of early disease progression may require earlier therapeutic review."

Researchers identify clinical and MRI biomarkers that may help predict outcomes in patients with relapsing-remitting MS up to eight years after starting therapy.

HONOLULU—Higher brain volume at baseline and a greater medication possession ratio predicted improved long-term clinical outcomes among patients with relapsing-remitting multiple sclerosis (MS), according to research presented at the 63rd Annual Meeting of the American Academy of Neurology. In addition, a higher baseline Expanded Disability Status Scale (EDSS) score and a greater early increase in EDSS score predicted worse outcomes, researchers reported.

“Given the heterogeneous nature of MS, it is important to identify prognostic factors that may predict outcomes as long as eight years after starting therapy,” stated Anthony Traboulsee, MD, Assistant Professor of Neurology at the University of British Columbia in Vancouver, and colleagues. “Assessing baseline brain volume and closely monitoring early disability status may be important to consider in monitoring and treatment decisions.”

Long-Term Follow-Up After Treatment Initiation
Dr. Traboulsee’s group conducted the Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) long-term follow-up (LTFU) study to analyze early clinical and MRI variables as predictors of long-term outcomes in patients with relapsing-remitting MS. The PRISMS LTFU cohort was followed prospectively for as long as eight years, with a 68% patient return rate in the follow-up. “Assessment protocols remained consistent through the course of the PRISMS study, thereby providing one of the most complete datasets of its type available,” noted the investigators.

A total of 382 patients were included in the LTFU follow-up to PRISMS, in which 560 patients were originally randomized. Among the 382 patients in the LTFU, 136 patients had been initially randomized to receive interferon beta-1a 44 µg; 123 patients had received interferon beta-1a 22 µg subcutaneously three times per week; and 123 participants had received placebo. Post-hoc exploratory analyses were conducted on data collected from all LTFU patients and in the subcohort originally randomized to receive subcutaneous interferon beta-1a, who were referred to as early-start patients (n = 259).

Baseline variables and medication possession ratio, as an indicator of subcutaneous interferon beta-1a treatment exposure, were explored as candidate prognostic factors for outcomes measured from baseline to LTFU (for up to eight years). The authors also investigated indicators of early clinical and MRI activity from baseline to month 24 as candidate prognostic factors for outcomes measured from month 24 to LTFU.
Predicting Favorable and Unfavorable Outcomes in MS
The researchers found that age, duration of MS, baseline EDSS score, baseline log (T2 disease of burden), and baseline brain volume were univariate predictors for nearly all long-term outcomes as measured from baseline to LTFU among all patients and early-start patients. Medication possession ratio predicted most of the long-term outcomes measured from baseline to LTFU in all patients and was a predictor for several outcomes in early-start patients.

Early change in EDSS score up to two years was a univariate predictor for virtually all outcomes measured from month 24 to LTFU in all patients and early-start patients, according to the investigators. In addition, EDSS progression and the number of EDSS progressions during the first 24 months were  frequent predictors for clinical outcomes as measured from month 24 to LTFU in all patients and early-start patients.

“The early MRI activity indicators were significant univariate predictors of several long-term disability outcomes, but not as frequently as seen with early EDSS progression,” reported Dr. Traboulsee and colleagues. “Brain volumes at baseline continued to be a predictor in all final multivariate models for all long-term clinical outcomes in both patient groups measured from baseline to LTFU. EDSS score at baseline continued to be a predictor in most multivariate models in both patient groups measured from baseline to LTFU.”

In several multivariate models, medication possession ratio continued to be a predictor for all long-term clinical outcomes in the all-patient cohort measured from baseline to LTFU, noted the investigators. The change in EDSS score from baseline to month 24 continued to be a predictor in nearly all final multivariate models for long-term clinical outcomes in all patients, and in all final multivariate models for all long-term clinical outcomes in early-start patients. Also, short-term MRI activity was predictive of some of the long-term clinical outcomes.

“These data suggest that a good early clinical response—no EDSS progression—can be predictive of a favorable long-term outcome,” Dr. Traboulsee and colleagues concluded. “However, patients who show worrisome signs of early disease progression may require earlier therapeutic review."

Researchers identify clinical and MRI biomarkers that may help predict outcomes in patients with relapsing-remitting MS up to eight years after starting therapy.

HONOLULU—Higher brain volume at baseline and a greater medication possession ratio predicted improved long-term clinical outcomes among patients with relapsing-remitting multiple sclerosis (MS), according to research presented at the 63rd Annual Meeting of the American Academy of Neurology. In addition, a higher baseline Expanded Disability Status Scale (EDSS) score and a greater early increase in EDSS score predicted worse outcomes, researchers reported.

“Given the heterogeneous nature of MS, it is important to identify prognostic factors that may predict outcomes as long as eight years after starting therapy,” stated Anthony Traboulsee, MD, Assistant Professor of Neurology at the University of British Columbia in Vancouver, and colleagues. “Assessing baseline brain volume and closely monitoring early disability status may be important to consider in monitoring and treatment decisions.”

Long-Term Follow-Up After Treatment Initiation
Dr. Traboulsee’s group conducted the Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) long-term follow-up (LTFU) study to analyze early clinical and MRI variables as predictors of long-term outcomes in patients with relapsing-remitting MS. The PRISMS LTFU cohort was followed prospectively for as long as eight years, with a 68% patient return rate in the follow-up. “Assessment protocols remained consistent through the course of the PRISMS study, thereby providing one of the most complete datasets of its type available,” noted the investigators.

A total of 382 patients were included in the LTFU follow-up to PRISMS, in which 560 patients were originally randomized. Among the 382 patients in the LTFU, 136 patients had been initially randomized to receive interferon beta-1a 44 µg; 123 patients had received interferon beta-1a 22 µg subcutaneously three times per week; and 123 participants had received placebo. Post-hoc exploratory analyses were conducted on data collected from all LTFU patients and in the subcohort originally randomized to receive subcutaneous interferon beta-1a, who were referred to as early-start patients (n = 259).

Baseline variables and medication possession ratio, as an indicator of subcutaneous interferon beta-1a treatment exposure, were explored as candidate prognostic factors for outcomes measured from baseline to LTFU (for up to eight years). The authors also investigated indicators of early clinical and MRI activity from baseline to month 24 as candidate prognostic factors for outcomes measured from month 24 to LTFU.
Predicting Favorable and Unfavorable Outcomes in MS
The researchers found that age, duration of MS, baseline EDSS score, baseline log (T2 disease of burden), and baseline brain volume were univariate predictors for nearly all long-term outcomes as measured from baseline to LTFU among all patients and early-start patients. Medication possession ratio predicted most of the long-term outcomes measured from baseline to LTFU in all patients and was a predictor for several outcomes in early-start patients.

Early change in EDSS score up to two years was a univariate predictor for virtually all outcomes measured from month 24 to LTFU in all patients and early-start patients, according to the investigators. In addition, EDSS progression and the number of EDSS progressions during the first 24 months were  frequent predictors for clinical outcomes as measured from month 24 to LTFU in all patients and early-start patients.

“The early MRI activity indicators were significant univariate predictors of several long-term disability outcomes, but not as frequently as seen with early EDSS progression,” reported Dr. Traboulsee and colleagues. “Brain volumes at baseline continued to be a predictor in all final multivariate models for all long-term clinical outcomes in both patient groups measured from baseline to LTFU. EDSS score at baseline continued to be a predictor in most multivariate models in both patient groups measured from baseline to LTFU.”

In several multivariate models, medication possession ratio continued to be a predictor for all long-term clinical outcomes in the all-patient cohort measured from baseline to LTFU, noted the investigators. The change in EDSS score from baseline to month 24 continued to be a predictor in nearly all final multivariate models for long-term clinical outcomes in all patients, and in all final multivariate models for all long-term clinical outcomes in early-start patients. Also, short-term MRI activity was predictive of some of the long-term clinical outcomes.

“These data suggest that a good early clinical response—no EDSS progression—can be predictive of a favorable long-term outcome,” Dr. Traboulsee and colleagues concluded. “However, patients who show worrisome signs of early disease progression may require earlier therapeutic review."

A majority of patients with neuromyelitis optica also experience disease-specific brain lesions that could help distinguish neuromyelitis optica from multiple sclerosis.

MONTREAL—Imaging studies of patients with neuromyelitis optica (NMO)–spectrum disorders reveal that effects of the aquaporin-4 (AQP4) autoantibody, a marker of the disease, may extend beyond the spinal cord and optic nerve, according to researchers. MRI findings of these disease-specific lesions may make it possible to differentiate between NMO and multiple sclerosis (MS).
Jose A. Cabrera-Gomez, MD, PhD, of the Multiple Sclerosis Clinic International Neurologic Restoration Center and Cuban Multiple Sclerosis Society in Havana, and Ilya Kister, MD, from the New York University School of Medicine, presented their findings at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
“Antibody to aquaporin-4 (AQP4) is a marker of relapsing NMO with specificity that approaches 100%,” the authors wrote. “Since AQP4 is distributed widely throughout the brain, especially in the ependyma and microvessels, one might expect that NMO would affect not only spinal cord and optic nerves, but brain as well.”
Frequency of Brain Abnormalities in Patients With NMO
To examine the extent of brain involvement in NMO, the researchers reviewed 18 case series (involving approximately 500 patients) that used MRI to document brain abnormalities in patients with NMO-spectrum disorders. The cases were divided into three groups: adult NMO (10), pediatric NMO (5), and anti-AQP4–positive patients (4).
“The frequency of brain abnormalities ranged from 43% to 100%,” Drs. Cabrera-Gomez and Kister reported. Differences in disease expression across ethnic groups, varying time from symptom onset to brain MRI, and methodological differences could contribute to this wide range of findings, they noted.
The authors reported finding striking convergent findings across multiple research groups. “Brain lesions on MRI are very common in NMO and are seen in the majority of patients with prolonged disease duration,” Dr. Lister told Neurology Reviews. “Certain lesion types appear to be typical for NMO and atypical for MS and these could potentially be useful to differentiate NMO from MS.” Lesion types that were typical of NMO included callosal/septal interface lesions, Balo-like lesions in the pons, and cavitary lesions in the occipital lobe. The researchers also noted that AQP4-seropositive patients were more likely to have brain lesions.
Can MRI Findings Differentiate Between NMO and MS?
“Brain lesions are seen in many NMO patients at onset of the disease, and in the majority of NMO patients on follow-up imaging,” the investigators wrote. This study’s findings and the discovery of NMO-specific lesions could lead to the development of diagnostic criteria for the disease.
“We advocate for systematic, prospective, multicenter studies to further characterize evolution of brain lesions in NMO and development of consensus criteria of brain MRI findings that could assist in differentiating NMO from MS,” the authors stated. This entails developing criteria that incorporate both positive brain MRI findings (“typical NMO lesions/high positive predictive value”) and negative brain MRI findings (“atypical in NMO/high negative predictive value”). “Studies are needed to determine sensitivity and specificity of various brain MRI findings for diagnosis of NMO,” said Dr. Lister. “A substantial minority of NMO patients have brain abnormalities that fulfill Barkhoff criteria for dissemination in space in MS. Thus, current MRI criteria for MS cannot be used to definitively differentiate MS from NMO.”

A majority of patients with neuromyelitis optica also experience disease-specific brain lesions that could help distinguish neuromyelitis optica from multiple sclerosis.

MONTREAL—Imaging studies of patients with neuromyelitis optica (NMO)–spectrum disorders reveal that effects of the aquaporin-4 (AQP4) autoantibody, a marker of the disease, may extend beyond the spinal cord and optic nerve, according to researchers. MRI findings of these disease-specific lesions may make it possible to differentiate between NMO and multiple sclerosis (MS).
Jose A. Cabrera-Gomez, MD, PhD, of the Multiple Sclerosis Clinic International Neurologic Restoration Center and Cuban Multiple Sclerosis Society in Havana, and Ilya Kister, MD, from the New York University School of Medicine, presented their findings at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
“Antibody to aquaporin-4 (AQP4) is a marker of relapsing NMO with specificity that approaches 100%,” the authors wrote. “Since AQP4 is distributed widely throughout the brain, especially in the ependyma and microvessels, one might expect that NMO would affect not only spinal cord and optic nerves, but brain as well.”
Frequency of Brain Abnormalities in Patients With NMO
To examine the extent of brain involvement in NMO, the researchers reviewed 18 case series (involving approximately 500 patients) that used MRI to document brain abnormalities in patients with NMO-spectrum disorders. The cases were divided into three groups: adult NMO (10), pediatric NMO (5), and anti-AQP4–positive patients (4).
“The frequency of brain abnormalities ranged from 43% to 100%,” Drs. Cabrera-Gomez and Kister reported. Differences in disease expression across ethnic groups, varying time from symptom onset to brain MRI, and methodological differences could contribute to this wide range of findings, they noted.
The authors reported finding striking convergent findings across multiple research groups. “Brain lesions on MRI are very common in NMO and are seen in the majority of patients with prolonged disease duration,” Dr. Lister told Neurology Reviews. “Certain lesion types appear to be typical for NMO and atypical for MS and these could potentially be useful to differentiate NMO from MS.” Lesion types that were typical of NMO included callosal/septal interface lesions, Balo-like lesions in the pons, and cavitary lesions in the occipital lobe. The researchers also noted that AQP4-seropositive patients were more likely to have brain lesions.
Can MRI Findings Differentiate Between NMO and MS?
“Brain lesions are seen in many NMO patients at onset of the disease, and in the majority of NMO patients on follow-up imaging,” the investigators wrote. This study’s findings and the discovery of NMO-specific lesions could lead to the development of diagnostic criteria for the disease.
“We advocate for systematic, prospective, multicenter studies to further characterize evolution of brain lesions in NMO and development of consensus criteria of brain MRI findings that could assist in differentiating NMO from MS,” the authors stated. This entails developing criteria that incorporate both positive brain MRI findings (“typical NMO lesions/high positive predictive value”) and negative brain MRI findings (“atypical in NMO/high negative predictive value”). “Studies are needed to determine sensitivity and specificity of various brain MRI findings for diagnosis of NMO,” said Dr. Lister. “A substantial minority of NMO patients have brain abnormalities that fulfill Barkhoff criteria for dissemination in space in MS. Thus, current MRI criteria for MS cannot be used to definitively differentiate MS from NMO.”

A majority of patients with neuromyelitis optica also experience disease-specific brain lesions that could help distinguish neuromyelitis optica from multiple sclerosis.

MONTREAL—Imaging studies of patients with neuromyelitis optica (NMO)–spectrum disorders reveal that effects of the aquaporin-4 (AQP4) autoantibody, a marker of the disease, may extend beyond the spinal cord and optic nerve, according to researchers. MRI findings of these disease-specific lesions may make it possible to differentiate between NMO and multiple sclerosis (MS).
Jose A. Cabrera-Gomez, MD, PhD, of the Multiple Sclerosis Clinic International Neurologic Restoration Center and Cuban Multiple Sclerosis Society in Havana, and Ilya Kister, MD, from the New York University School of Medicine, presented their findings at the 25th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
“Antibody to aquaporin-4 (AQP4) is a marker of relapsing NMO with specificity that approaches 100%,” the authors wrote. “Since AQP4 is distributed widely throughout the brain, especially in the ependyma and microvessels, one might expect that NMO would affect not only spinal cord and optic nerves, but brain as well.”
Frequency of Brain Abnormalities in Patients With NMO
To examine the extent of brain involvement in NMO, the researchers reviewed 18 case series (involving approximately 500 patients) that used MRI to document brain abnormalities in patients with NMO-spectrum disorders. The cases were divided into three groups: adult NMO (10), pediatric NMO (5), and anti-AQP4–positive patients (4).
“The frequency of brain abnormalities ranged from 43% to 100%,” Drs. Cabrera-Gomez and Kister reported. Differences in disease expression across ethnic groups, varying time from symptom onset to brain MRI, and methodological differences could contribute to this wide range of findings, they noted.
The authors reported finding striking convergent findings across multiple research groups. “Brain lesions on MRI are very common in NMO and are seen in the majority of patients with prolonged disease duration,” Dr. Lister told Neurology Reviews. “Certain lesion types appear to be typical for NMO and atypical for MS and these could potentially be useful to differentiate NMO from MS.” Lesion types that were typical of NMO included callosal/septal interface lesions, Balo-like lesions in the pons, and cavitary lesions in the occipital lobe. The researchers also noted that AQP4-seropositive patients were more likely to have brain lesions.
Can MRI Findings Differentiate Between NMO and MS?
“Brain lesions are seen in many NMO patients at onset of the disease, and in the majority of NMO patients on follow-up imaging,” the investigators wrote. This study’s findings and the discovery of NMO-specific lesions could lead to the development of diagnostic criteria for the disease.
“We advocate for systematic, prospective, multicenter studies to further characterize evolution of brain lesions in NMO and development of consensus criteria of brain MRI findings that could assist in differentiating NMO from MS,” the authors stated. This entails developing criteria that incorporate both positive brain MRI findings (“typical NMO lesions/high positive predictive value”) and negative brain MRI findings (“atypical in NMO/high negative predictive value”). “Studies are needed to determine sensitivity and specificity of various brain MRI findings for diagnosis of NMO,” said Dr. Lister. “A substantial minority of NMO patients have brain abnormalities that fulfill Barkhoff criteria for dissemination in space in MS. Thus, current MRI criteria for MS cannot be used to definitively differentiate MS from NMO.”

Vascular conditions, including atherosclerosis, may play an important role in the development of cognitive impairment and dementia, according to a report published online in the July 21 Stroke. The authors used previously published guidelines and literature, as well as personal experience, to summarize existing evidence, indicate gaps in current knowledge, and formulate recommendations regarding vascular contributions to cognitive decline late in life. Observed vascular risk factors included atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia, all of which, the researchers noted, were also risk factors for stroke and Alzheimer’s disease. “The neuropathology of cognitive impairment later in life is often a mixture of Alzheimer’s disease and microvascular brain damage,” the authors wrote. “Detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of vascular cognitive impairment, even in older people.”
Women with epilepsy experience greater seizure frequency during anovulatory cycles than during cycles when ovulation occurs, according to results of a study published July 14 online ahead of print in Epilepsia. Almost 300 women with epilepsy were enrolled in the study; 92 had completed both cycles during the study period. Their average daily seizure frequency, seizure type, and progesterone/estradiol serum level ratios were recorded. “Average daily seizure frequency was 29.5% greater for secondary generalized tonic-clonic seizures during anovulatory than during ovulatory cycles,” the researchers wrote. Frequency did not differ significantly for complex or simple partial seizures, or for all seizure types combined. “Because the proportional increases in secondary generalized tonic-clonic seizure frequency during anovulatory cycles correlate with the proportional increases in estradiol/progesterone serum level ratios, these findings support a possible role for reproductive steroids in [seizure] occurrence.”
Researchers have identified a new genetic risk factor for restless legs syndrome (RLS), as reported in the July 14 PLoS Genetics. The authors conducted a genome-wide association study of 922 patients with RLS, and compared the results with 1,526 controls. The researchers included 301,406 single nucleotide polymorphisms (SNPs) in the study, followed by a replication of 76 candidate SNPs in 3,935 patients and 5,754 controls. “We identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972) and a locus on 16q12.1 (rs3104767) in a linkage disequilibrium block of 40 kb containing the 5´-end of TOX3 and the adjacent noncoding RNA BC034767,” the investigators reported. They concluded, “The physiologic role of TOX3 and BC034767 in the CNS and a possible involvement of these two genes in RLS pathogenesis remain to be established.”
Breastfeeding does not significantly provide protection against postpartum relapses in women with multiple sclerosis (MS), a finding that contradicts results from previous studies, researchers reported in the July 12 Neurology. The investigators prospectively followed up pregnancies in 298 women with MS and gathered data on breastfeeding; they monitored relapse rates for up to one year after delivery. “The time-dependent profile of the relapse rate before, during, and after pregnancy did not differ between patients who breastfed and patients who did not,” the authors reported. The only significant predictors of postpartum relapses were relapses before and during pregnancy. “Therefore, the reported association between breastfeeding and a lower risk of postpartum relapses may simply reflect different patient behavior, biased by the disease activity,” the investigators concluded.
Low bone density and osteoporosis commonly appear in the early stages of multiple sclerosis (MS), according to a study published in the July 12 Neurology. “If vitamin D exerts a major effect on MS risk,” the investigators hypothesized, “skeletal consequences of hypovitaminosis D could be apparent shortly after the onset of MS.” To test their hypothesis, the researchers measured the bone mineral density of 99 patients in the early stages of the disease with no or minor disability; these results were compared with the densities of 159 healthy controls. Half of the patients had either osteopenia or osteoporosis, compared with 37.1% of the controls. “[This finding is] compatible with shared etiologic or pathogenic factors in MS and osteoporosis, and calls for an active approach to optimize bone health in early stages of MS,” the authors concluded.
According to a study published in the July 12 online BMJ, there is no significant link between adjuvanted vaccines used during the 2009 swine flu pandemic and Guillain-Barré syndrome. The investigators performed a case-control study in five European countries of 104 patients with the syndrome and age-, sex-, and location-matched controls. The initial, unadjusted pooled risk estimate for all countries was 2.8, and case recruitment and vaccine coverage varied considerably between countries. “After adjustment for influenza-like illness/upper respiratory tract infection and seasonal influenza vaccination, receipt of pandemic influenza vaccine was not associated with an increased risk of Guillain-Barré syndrome,” the investigators reported. They did note, however, “the upper limit does not exclude a potential increase in risk up to 2.7-fold or three excess cases per one million vaccinated people.”
A team of researchers has found a genetic determinant of late-onset Parkinson’s disease, according to a study published in the July 9 issue of American Journal of Human Genetics. “To identify rare causal variants in late-onset Parkinson’s disease, we investigated an Austrian family with 16 affected individuals by exome sequencing,” the investigators explained. “We found a missense mutation, c.1858G>A, in the VPS35 gene in all seven affected family members who are alive.” Screening the entire VPS35 coding sequence in additional Parkinson’s disease cases and controls revealed six other missense variants; three were only present in patients, two were only present in controls, and one was present in both groups. The investigators also noted, “VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer’s disease.”
Researchers have found that African-American patients with ischemic stroke are significantly less likely to be treated with IV t-PA, due to delayed presentation and stroke severity, according to a study published in the June 30 online Stroke. The investigators performed a systematic chart review on patients admitted to seven Washington, DC–area hospitals; of 1,044 patients with ischemic stroke, 74% were black and 5% received t-PA. African-American patients were one-third less likely than white patients to receive IV t-PA, were less likely to present at the hospital within three hours of symptom onset, and were less likely to be eligible for t-PA treatment. African-American patients also had a greater rate of contraindications to t-PA treatment, including hypertension, recent stroke, or use of blood thinners.
People with a history of traumatic brain injury (TBI) are more likely to develop long-term neurodegeneration than those who have never experienced a brain injury, according to research appearing in the June 29 online Brain Pathology. Investigators examined postmortem brains from 39 survivors of a single TBI and 47 brains of uninjured, age-matched controls using immunochemistry and thioflavin-S staining. “Neurofibrillary tangles were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one-third of TBI cases,” the researchers reported. In addition, patients with TBI had a greater density of amyloid-beta plaques than controls. “These data demonstrate widespread neurofibrillary tangles and amyloid-beta plaque pathologies are present in a proportion of patients following a single TBI, suggesting that some individuals who experience a single TBI may develop long-term neuropathological changes akin to those found in neurodegenerative disease,” the authors concluded.
A group of researchers presented a new set of practice guidelines regarding genetic counseling, as reported in the June Genetics in Medicine. The guidelines, developed through a joint effort by the American College of Medical Genetics and the National Society of Genetic Counselors, seek to provide medical professionals with guidance in the complex area of genetic testing. “Despite its limited utility, patients express concern over their risk and, in some instances, request testing,” the authors wrote. “This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer’s disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for Alzheimer’s disease,” they concluded.
Regions important for cognitive and motor control are smaller in the brains of children with attention-deficit hyperactivity disorder (ADHD) than in typically developing children, researchers reported in the June 9 online Clinical Neuropsychologist. To understand the neurobiologic development of ADHD, the investigators examined high-resolution anatomic images of 13 children with ADHD and 13 controls (ages 4 to 5). “Children with ADHD showed significantly reduced caudate volumes bilaterally; in contrast there were no significant group differences in cortical volume or thickness in this range,” the authors observed. Left caudate volume was a significant predictor of hyperactive and impulsive symptom severity, but not inattention. “Anomalous basal ganglia, particularly caudate, development appears to play an important role among children presenting with early onset symptoms of ADHD,” the researchers concluded.
A diet low in saturated fat and simple carbohydrates may modulate the risk of developing dementia that precedes Alzheimer’s disease, researchers reported in the June Archives of Neurology. To compare the effects of different diets on insulin and lipid metabolism, CSF markers of Alzheimer’s disease, and cognition, the investigators randomized 20 healthy adults and 29 adults with amnestic mild cognitive impairment to either a high- or low-fat and glycemic index diet. In the cognitively impaired group, the “low” diet increased CSF amyloid-beta 42 concentrations; the opposite was true for healthy patients on this diet. For both groups, the “low” diet improved visual memory. “Diet may be a powerful environmental factor that modulates Alzheimer’s disease risk through its effects on CNS concentrations of amyloid-beta 42, lipoproteins, oxidative stress, and insulin,” the investigators concluded.
A study in the June Headache found that prophylactic medications and behavioral interventions for migraine are cost-competitive and cost-efficient options during the early phases of treatment. Researchers distributed surveys to physicians and behavioral specialists to gather data about costs of prototypical regimens for preventive pharmacologic treatment, clinic-based behavioral treatment, minimal contact behavioral treatment, and group behavioral treatment. During the initial months of treatment, pharmacologic treatment with inexpensive medications was the least costly option (

Vascular conditions, including atherosclerosis, may play an important role in the development of cognitive impairment and dementia, according to a report published online in the July 21 Stroke. The authors used previously published guidelines and literature, as well as personal experience, to summarize existing evidence, indicate gaps in current knowledge, and formulate recommendations regarding vascular contributions to cognitive decline late in life. Observed vascular risk factors included atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia, all of which, the researchers noted, were also risk factors for stroke and Alzheimer’s disease. “The neuropathology of cognitive impairment later in life is often a mixture of Alzheimer’s disease and microvascular brain damage,” the authors wrote. “Detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of vascular cognitive impairment, even in older people.”
Women with epilepsy experience greater seizure frequency during anovulatory cycles than during cycles when ovulation occurs, according to results of a study published July 14 online ahead of print in Epilepsia. Almost 300 women with epilepsy were enrolled in the study; 92 had completed both cycles during the study period. Their average daily seizure frequency, seizure type, and progesterone/estradiol serum level ratios were recorded. “Average daily seizure frequency was 29.5% greater for secondary generalized tonic-clonic seizures during anovulatory than during ovulatory cycles,” the researchers wrote. Frequency did not differ significantly for complex or simple partial seizures, or for all seizure types combined. “Because the proportional increases in secondary generalized tonic-clonic seizure frequency during anovulatory cycles correlate with the proportional increases in estradiol/progesterone serum level ratios, these findings support a possible role for reproductive steroids in [seizure] occurrence.”
Researchers have identified a new genetic risk factor for restless legs syndrome (RLS), as reported in the July 14 PLoS Genetics. The authors conducted a genome-wide association study of 922 patients with RLS, and compared the results with 1,526 controls. The researchers included 301,406 single nucleotide polymorphisms (SNPs) in the study, followed by a replication of 76 candidate SNPs in 3,935 patients and 5,754 controls. “We identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972) and a locus on 16q12.1 (rs3104767) in a linkage disequilibrium block of 40 kb containing the 5´-end of TOX3 and the adjacent noncoding RNA BC034767,” the investigators reported. They concluded, “The physiologic role of TOX3 and BC034767 in the CNS and a possible involvement of these two genes in RLS pathogenesis remain to be established.”
Breastfeeding does not significantly provide protection against postpartum relapses in women with multiple sclerosis (MS), a finding that contradicts results from previous studies, researchers reported in the July 12 Neurology. The investigators prospectively followed up pregnancies in 298 women with MS and gathered data on breastfeeding; they monitored relapse rates for up to one year after delivery. “The time-dependent profile of the relapse rate before, during, and after pregnancy did not differ between patients who breastfed and patients who did not,” the authors reported. The only significant predictors of postpartum relapses were relapses before and during pregnancy. “Therefore, the reported association between breastfeeding and a lower risk of postpartum relapses may simply reflect different patient behavior, biased by the disease activity,” the investigators concluded.
Low bone density and osteoporosis commonly appear in the early stages of multiple sclerosis (MS), according to a study published in the July 12 Neurology. “If vitamin D exerts a major effect on MS risk,” the investigators hypothesized, “skeletal consequences of hypovitaminosis D could be apparent shortly after the onset of MS.” To test their hypothesis, the researchers measured the bone mineral density of 99 patients in the early stages of the disease with no or minor disability; these results were compared with the densities of 159 healthy controls. Half of the patients had either osteopenia or osteoporosis, compared with 37.1% of the controls. “[This finding is] compatible with shared etiologic or pathogenic factors in MS and osteoporosis, and calls for an active approach to optimize bone health in early stages of MS,” the authors concluded.
According to a study published in the July 12 online BMJ, there is no significant link between adjuvanted vaccines used during the 2009 swine flu pandemic and Guillain-Barré syndrome. The investigators performed a case-control study in five European countries of 104 patients with the syndrome and age-, sex-, and location-matched controls. The initial, unadjusted pooled risk estimate for all countries was 2.8, and case recruitment and vaccine coverage varied considerably between countries. “After adjustment for influenza-like illness/upper respiratory tract infection and seasonal influenza vaccination, receipt of pandemic influenza vaccine was not associated with an increased risk of Guillain-Barré syndrome,” the investigators reported. They did note, however, “the upper limit does not exclude a potential increase in risk up to 2.7-fold or three excess cases per one million vaccinated people.”
A team of researchers has found a genetic determinant of late-onset Parkinson’s disease, according to a study published in the July 9 issue of American Journal of Human Genetics. “To identify rare causal variants in late-onset Parkinson’s disease, we investigated an Austrian family with 16 affected individuals by exome sequencing,” the investigators explained. “We found a missense mutation, c.1858G>A, in the VPS35 gene in all seven affected family members who are alive.” Screening the entire VPS35 coding sequence in additional Parkinson’s disease cases and controls revealed six other missense variants; three were only present in patients, two were only present in controls, and one was present in both groups. The investigators also noted, “VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer’s disease.”
Researchers have found that African-American patients with ischemic stroke are significantly less likely to be treated with IV t-PA, due to delayed presentation and stroke severity, according to a study published in the June 30 online Stroke. The investigators performed a systematic chart review on patients admitted to seven Washington, DC–area hospitals; of 1,044 patients with ischemic stroke, 74% were black and 5% received t-PA. African-American patients were one-third less likely than white patients to receive IV t-PA, were less likely to present at the hospital within three hours of symptom onset, and were less likely to be eligible for t-PA treatment. African-American patients also had a greater rate of contraindications to t-PA treatment, including hypertension, recent stroke, or use of blood thinners.
People with a history of traumatic brain injury (TBI) are more likely to develop long-term neurodegeneration than those who have never experienced a brain injury, according to research appearing in the June 29 online Brain Pathology. Investigators examined postmortem brains from 39 survivors of a single TBI and 47 brains of uninjured, age-matched controls using immunochemistry and thioflavin-S staining. “Neurofibrillary tangles were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one-third of TBI cases,” the researchers reported. In addition, patients with TBI had a greater density of amyloid-beta plaques than controls. “These data demonstrate widespread neurofibrillary tangles and amyloid-beta plaque pathologies are present in a proportion of patients following a single TBI, suggesting that some individuals who experience a single TBI may develop long-term neuropathological changes akin to those found in neurodegenerative disease,” the authors concluded.
A group of researchers presented a new set of practice guidelines regarding genetic counseling, as reported in the June Genetics in Medicine. The guidelines, developed through a joint effort by the American College of Medical Genetics and the National Society of Genetic Counselors, seek to provide medical professionals with guidance in the complex area of genetic testing. “Despite its limited utility, patients express concern over their risk and, in some instances, request testing,” the authors wrote. “This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer’s disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for Alzheimer’s disease,” they concluded.
Regions important for cognitive and motor control are smaller in the brains of children with attention-deficit hyperactivity disorder (ADHD) than in typically developing children, researchers reported in the June 9 online Clinical Neuropsychologist. To understand the neurobiologic development of ADHD, the investigators examined high-resolution anatomic images of 13 children with ADHD and 13 controls (ages 4 to 5). “Children with ADHD showed significantly reduced caudate volumes bilaterally; in contrast there were no significant group differences in cortical volume or thickness in this range,” the authors observed. Left caudate volume was a significant predictor of hyperactive and impulsive symptom severity, but not inattention. “Anomalous basal ganglia, particularly caudate, development appears to play an important role among children presenting with early onset symptoms of ADHD,” the researchers concluded.
A diet low in saturated fat and simple carbohydrates may modulate the risk of developing dementia that precedes Alzheimer’s disease, researchers reported in the June Archives of Neurology. To compare the effects of different diets on insulin and lipid metabolism, CSF markers of Alzheimer’s disease, and cognition, the investigators randomized 20 healthy adults and 29 adults with amnestic mild cognitive impairment to either a high- or low-fat and glycemic index diet. In the cognitively impaired group, the “low” diet increased CSF amyloid-beta 42 concentrations; the opposite was true for healthy patients on this diet. For both groups, the “low” diet improved visual memory. “Diet may be a powerful environmental factor that modulates Alzheimer’s disease risk through its effects on CNS concentrations of amyloid-beta 42, lipoproteins, oxidative stress, and insulin,” the investigators concluded.
A study in the June Headache found that prophylactic medications and behavioral interventions for migraine are cost-competitive and cost-efficient options during the early phases of treatment. Researchers distributed surveys to physicians and behavioral specialists to gather data about costs of prototypical regimens for preventive pharmacologic treatment, clinic-based behavioral treatment, minimal contact behavioral treatment, and group behavioral treatment. During the initial months of treatment, pharmacologic treatment with inexpensive medications was the least costly option (

Vascular conditions, including atherosclerosis, may play an important role in the development of cognitive impairment and dementia, according to a report published online in the July 21 Stroke. The authors used previously published guidelines and literature, as well as personal experience, to summarize existing evidence, indicate gaps in current knowledge, and formulate recommendations regarding vascular contributions to cognitive decline late in life. Observed vascular risk factors included atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia, all of which, the researchers noted, were also risk factors for stroke and Alzheimer’s disease. “The neuropathology of cognitive impairment later in life is often a mixture of Alzheimer’s disease and microvascular brain damage,” the authors wrote. “Detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of vascular cognitive impairment, even in older people.”
Women with epilepsy experience greater seizure frequency during anovulatory cycles than during cycles when ovulation occurs, according to results of a study published July 14 online ahead of print in Epilepsia. Almost 300 women with epilepsy were enrolled in the study; 92 had completed both cycles during the study period. Their average daily seizure frequency, seizure type, and progesterone/estradiol serum level ratios were recorded. “Average daily seizure frequency was 29.5% greater for secondary generalized tonic-clonic seizures during anovulatory than during ovulatory cycles,” the researchers wrote. Frequency did not differ significantly for complex or simple partial seizures, or for all seizure types combined. “Because the proportional increases in secondary generalized tonic-clonic seizure frequency during anovulatory cycles correlate with the proportional increases in estradiol/progesterone serum level ratios, these findings support a possible role for reproductive steroids in [seizure] occurrence.”
Researchers have identified a new genetic risk factor for restless legs syndrome (RLS), as reported in the July 14 PLoS Genetics. The authors conducted a genome-wide association study of 922 patients with RLS, and compared the results with 1,526 controls. The researchers included 301,406 single nucleotide polymorphisms (SNPs) in the study, followed by a replication of 76 candidate SNPs in 3,935 patients and 5,754 controls. “We identified six RLS susceptibility loci of genome-wide significance, two of them novel: an intergenic region on chromosome 2p14 (rs6747972) and a locus on 16q12.1 (rs3104767) in a linkage disequilibrium block of 40 kb containing the 5´-end of TOX3 and the adjacent noncoding RNA BC034767,” the investigators reported. They concluded, “The physiologic role of TOX3 and BC034767 in the CNS and a possible involvement of these two genes in RLS pathogenesis remain to be established.”
Breastfeeding does not significantly provide protection against postpartum relapses in women with multiple sclerosis (MS), a finding that contradicts results from previous studies, researchers reported in the July 12 Neurology. The investigators prospectively followed up pregnancies in 298 women with MS and gathered data on breastfeeding; they monitored relapse rates for up to one year after delivery. “The time-dependent profile of the relapse rate before, during, and after pregnancy did not differ between patients who breastfed and patients who did not,” the authors reported. The only significant predictors of postpartum relapses were relapses before and during pregnancy. “Therefore, the reported association between breastfeeding and a lower risk of postpartum relapses may simply reflect different patient behavior, biased by the disease activity,” the investigators concluded.
Low bone density and osteoporosis commonly appear in the early stages of multiple sclerosis (MS), according to a study published in the July 12 Neurology. “If vitamin D exerts a major effect on MS risk,” the investigators hypothesized, “skeletal consequences of hypovitaminosis D could be apparent shortly after the onset of MS.” To test their hypothesis, the researchers measured the bone mineral density of 99 patients in the early stages of the disease with no or minor disability; these results were compared with the densities of 159 healthy controls. Half of the patients had either osteopenia or osteoporosis, compared with 37.1% of the controls. “[This finding is] compatible with shared etiologic or pathogenic factors in MS and osteoporosis, and calls for an active approach to optimize bone health in early stages of MS,” the authors concluded.
According to a study published in the July 12 online BMJ, there is no significant link between adjuvanted vaccines used during the 2009 swine flu pandemic and Guillain-Barré syndrome. The investigators performed a case-control study in five European countries of 104 patients with the syndrome and age-, sex-, and location-matched controls. The initial, unadjusted pooled risk estimate for all countries was 2.8, and case recruitment and vaccine coverage varied considerably between countries. “After adjustment for influenza-like illness/upper respiratory tract infection and seasonal influenza vaccination, receipt of pandemic influenza vaccine was not associated with an increased risk of Guillain-Barré syndrome,” the investigators reported. They did note, however, “the upper limit does not exclude a potential increase in risk up to 2.7-fold or three excess cases per one million vaccinated people.”
A team of researchers has found a genetic determinant of late-onset Parkinson’s disease, according to a study published in the July 9 issue of American Journal of Human Genetics. “To identify rare causal variants in late-onset Parkinson’s disease, we investigated an Austrian family with 16 affected individuals by exome sequencing,” the investigators explained. “We found a missense mutation, c.1858G>A, in the VPS35 gene in all seven affected family members who are alive.” Screening the entire VPS35 coding sequence in additional Parkinson’s disease cases and controls revealed six other missense variants; three were only present in patients, two were only present in controls, and one was present in both groups. The investigators also noted, “VPS35 is a component of the retromer complex and mediates retrograde transport between endosomes and the trans-Golgi network, and it has recently been found to be involved in Alzheimer’s disease.”
Researchers have found that African-American patients with ischemic stroke are significantly less likely to be treated with IV t-PA, due to delayed presentation and stroke severity, according to a study published in the June 30 online Stroke. The investigators performed a systematic chart review on patients admitted to seven Washington, DC–area hospitals; of 1,044 patients with ischemic stroke, 74% were black and 5% received t-PA. African-American patients were one-third less likely than white patients to receive IV t-PA, were less likely to present at the hospital within three hours of symptom onset, and were less likely to be eligible for t-PA treatment. African-American patients also had a greater rate of contraindications to t-PA treatment, including hypertension, recent stroke, or use of blood thinners.
People with a history of traumatic brain injury (TBI) are more likely to develop long-term neurodegeneration than those who have never experienced a brain injury, according to research appearing in the June 29 online Brain Pathology. Investigators examined postmortem brains from 39 survivors of a single TBI and 47 brains of uninjured, age-matched controls using immunochemistry and thioflavin-S staining. “Neurofibrillary tangles were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one-third of TBI cases,” the researchers reported. In addition, patients with TBI had a greater density of amyloid-beta plaques than controls. “These data demonstrate widespread neurofibrillary tangles and amyloid-beta plaque pathologies are present in a proportion of patients following a single TBI, suggesting that some individuals who experience a single TBI may develop long-term neuropathological changes akin to those found in neurodegenerative disease,” the authors concluded.
A group of researchers presented a new set of practice guidelines regarding genetic counseling, as reported in the June Genetics in Medicine. The guidelines, developed through a joint effort by the American College of Medical Genetics and the National Society of Genetic Counselors, seek to provide medical professionals with guidance in the complex area of genetic testing. “Despite its limited utility, patients express concern over their risk and, in some instances, request testing,” the authors wrote. “This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer’s disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for Alzheimer’s disease,” they concluded.
Regions important for cognitive and motor control are smaller in the brains of children with attention-deficit hyperactivity disorder (ADHD) than in typically developing children, researchers reported in the June 9 online Clinical Neuropsychologist. To understand the neurobiologic development of ADHD, the investigators examined high-resolution anatomic images of 13 children with ADHD and 13 controls (ages 4 to 5). “Children with ADHD showed significantly reduced caudate volumes bilaterally; in contrast there were no significant group differences in cortical volume or thickness in this range,” the authors observed. Left caudate volume was a significant predictor of hyperactive and impulsive symptom severity, but not inattention. “Anomalous basal ganglia, particularly caudate, development appears to play an important role among children presenting with early onset symptoms of ADHD,” the researchers concluded.
A diet low in saturated fat and simple carbohydrates may modulate the risk of developing dementia that precedes Alzheimer’s disease, researchers reported in the June Archives of Neurology. To compare the effects of different diets on insulin and lipid metabolism, CSF markers of Alzheimer’s disease, and cognition, the investigators randomized 20 healthy adults and 29 adults with amnestic mild cognitive impairment to either a high- or low-fat and glycemic index diet. In the cognitively impaired group, the “low” diet increased CSF amyloid-beta 42 concentrations; the opposite was true for healthy patients on this diet. For both groups, the “low” diet improved visual memory. “Diet may be a powerful environmental factor that modulates Alzheimer’s disease risk through its effects on CNS concentrations of amyloid-beta 42, lipoproteins, oxidative stress, and insulin,” the investigators concluded.
A study in the June Headache found that prophylactic medications and behavioral interventions for migraine are cost-competitive and cost-efficient options during the early phases of treatment. Researchers distributed surveys to physicians and behavioral specialists to gather data about costs of prototypical regimens for preventive pharmacologic treatment, clinic-based behavioral treatment, minimal contact behavioral treatment, and group behavioral treatment. During the initial months of treatment, pharmacologic treatment with inexpensive medications was the least costly option (

Statin Treatment Does Not Lower Risk for Recurrent Stroke in Patients With Type 2 Diabetes or Metabolic Syndrome
Patients with type 2 diabetes or metabolic syndrome did not benefit from treatment with atorvastatin, when compared with patients without either metabolic disorder, according to a study published in the June 13 online Archives of Neurology.
Alfred Callahan, MD, from the Vanderbilt University School of Medicine in Nashville, and colleagues conducted a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial to determine whether the effect of treatment on the primary end point (risk for stroke) and secondary end points (occurrence of coronary and cardiovascular events and procedures) varied based on the presence of type 2 diabetes or metabolic syndrome.
“The SPARCL trial found that statin treatment reduced stroke risk in patients with recent stroke or TIA and no known coronary heart disease (CHD),” Dr. Callahan’s group wrote. “No information is available, however, on the effect of statins on secondary stroke prevention in diabetic patients or in those with metabolic syndrome.”
Of the 4,731 subjects enrolled in the trial, 794 had diabetes and 642 had metabolic syndrome; 3,295 had neither condition and were included as the reference group. All patients were adults who had an ischemic or hemorrhagic stroke or TIA one to six months prior to randomization.
“The risk of stroke was 11.0% in the reference group, 18.1% in subjects with type 2 diabetes, and 10.7% in those with metabolic syndrome,” the investigators reported. “Subjects with type 2 diabetes mellitus were more likely to have any of the primary and secondary end points, including death.” Patients with metabolic syndrome had no increase in the risk of major cardiovascular events or major coronary events, but they were more likely to have any CHD event or revascularization procedure.
“In this post hoc analysis, we found that SPARCL subjects with type 2 diabetes mellitus were at higher risk for recurrent stroke and cardiovascular events but that there was no difference in the effect of statin treatment in reducing these events in subjects with or without type 2 diabetes or metabolic syndrome,” the authors concluded. They also noted that the possibility of variation on the benefit of statin treatment in subjects with or without type 2 diabetes or metabolic syndrome cannot be excluded by their analysis.
Callahan A, Amarenco P, Goldstein LB, et al. Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: Secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Arch Neurol. 2011 Jun 13; [Epub ahead of print].

Does Stress Increase the Risk for Multiple Sclerosis?
Daily life- and work-related stress and childhood trauma have no significant impact on increasing the risk of developing multiple sclerosis (MS), according to a study published in the May 31 issue of Neurology.
“Several studies have shown that stressful life events are associated with a subsequent significant increase in risk of MS exacerbations,” the authors wrote. “We wanted to study prospectively whether stress can increase the risk of developing the disease itself.”
Trond Riise, PhD, from the Department of Public Health and Primary Health Care at the University of Bergen in Norway, and colleagues analyzed questionnaires regarding stress at work and home and the effects of physical and sexual abuse in childhood and adolescence completed by women in the Nurses’ Health Study and Nurses’ Health Study II who developed MS during the study period. They then conducted separate analyses by levels of stress and by severity of childhood abuse to calculate incidence rates and hazard ratios of MS.
“Stress measurements were available for 77 of the 94 women who had developed MS,” the researchers reported. “Adjusting for age, ethnicity, latitude at birth, BMI at age 18, and biannually updated smoking status, there were no significant differences in the risk of MS between any of the levels of stress at home or at work.” Of the 292 women from the Nurses’ Health Study II who responded to questions about childhood trauma, 7% reported severe abuse; there was no significant increased risk.
The lack of a significant relationship between stress and trauma and the risk for MS could potentially be caused by the study’s retrospective design. “A major challenge when studying this relation is to achieve unbiased measurement of stress,” the authors explained. “The possibility that these assessments were not sensitive to the stressors and stress mechanisms that might increase risk of developing MS cannot be ruled out.
“These results do not support a major role of stress [for developing MS], but repeated and more focused measures of stress are needed to firmly exclude stress as a potential risk factor for MS,” the investigators concluded.
Riise T, Mohr DC, Munger KL, et al. Stress and the risk of multiple sclerosis. Neurology. 2011;76(22);1866-1871.

Statin Treatment Does Not Lower Risk for Recurrent Stroke in Patients With Type 2 Diabetes or Metabolic Syndrome
Patients with type 2 diabetes or metabolic syndrome did not benefit from treatment with atorvastatin, when compared with patients without either metabolic disorder, according to a study published in the June 13 online Archives of Neurology.
Alfred Callahan, MD, from the Vanderbilt University School of Medicine in Nashville, and colleagues conducted a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial to determine whether the effect of treatment on the primary end point (risk for stroke) and secondary end points (occurrence of coronary and cardiovascular events and procedures) varied based on the presence of type 2 diabetes or metabolic syndrome.
“The SPARCL trial found that statin treatment reduced stroke risk in patients with recent stroke or TIA and no known coronary heart disease (CHD),” Dr. Callahan’s group wrote. “No information is available, however, on the effect of statins on secondary stroke prevention in diabetic patients or in those with metabolic syndrome.”
Of the 4,731 subjects enrolled in the trial, 794 had diabetes and 642 had metabolic syndrome; 3,295 had neither condition and were included as the reference group. All patients were adults who had an ischemic or hemorrhagic stroke or TIA one to six months prior to randomization.
“The risk of stroke was 11.0% in the reference group, 18.1% in subjects with type 2 diabetes, and 10.7% in those with metabolic syndrome,” the investigators reported. “Subjects with type 2 diabetes mellitus were more likely to have any of the primary and secondary end points, including death.” Patients with metabolic syndrome had no increase in the risk of major cardiovascular events or major coronary events, but they were more likely to have any CHD event or revascularization procedure.
“In this post hoc analysis, we found that SPARCL subjects with type 2 diabetes mellitus were at higher risk for recurrent stroke and cardiovascular events but that there was no difference in the effect of statin treatment in reducing these events in subjects with or without type 2 diabetes or metabolic syndrome,” the authors concluded. They also noted that the possibility of variation on the benefit of statin treatment in subjects with or without type 2 diabetes or metabolic syndrome cannot be excluded by their analysis.
Callahan A, Amarenco P, Goldstein LB, et al. Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: Secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Arch Neurol. 2011 Jun 13; [Epub ahead of print].

Does Stress Increase the Risk for Multiple Sclerosis?
Daily life- and work-related stress and childhood trauma have no significant impact on increasing the risk of developing multiple sclerosis (MS), according to a study published in the May 31 issue of Neurology.
“Several studies have shown that stressful life events are associated with a subsequent significant increase in risk of MS exacerbations,” the authors wrote. “We wanted to study prospectively whether stress can increase the risk of developing the disease itself.”
Trond Riise, PhD, from the Department of Public Health and Primary Health Care at the University of Bergen in Norway, and colleagues analyzed questionnaires regarding stress at work and home and the effects of physical and sexual abuse in childhood and adolescence completed by women in the Nurses’ Health Study and Nurses’ Health Study II who developed MS during the study period. They then conducted separate analyses by levels of stress and by severity of childhood abuse to calculate incidence rates and hazard ratios of MS.
“Stress measurements were available for 77 of the 94 women who had developed MS,” the researchers reported. “Adjusting for age, ethnicity, latitude at birth, BMI at age 18, and biannually updated smoking status, there were no significant differences in the risk of MS between any of the levels of stress at home or at work.” Of the 292 women from the Nurses’ Health Study II who responded to questions about childhood trauma, 7% reported severe abuse; there was no significant increased risk.
The lack of a significant relationship between stress and trauma and the risk for MS could potentially be caused by the study’s retrospective design. “A major challenge when studying this relation is to achieve unbiased measurement of stress,” the authors explained. “The possibility that these assessments were not sensitive to the stressors and stress mechanisms that might increase risk of developing MS cannot be ruled out.
“These results do not support a major role of stress [for developing MS], but repeated and more focused measures of stress are needed to firmly exclude stress as a potential risk factor for MS,” the investigators concluded.
Riise T, Mohr DC, Munger KL, et al. Stress and the risk of multiple sclerosis. Neurology. 2011;76(22);1866-1871.

Statin Treatment Does Not Lower Risk for Recurrent Stroke in Patients With Type 2 Diabetes or Metabolic Syndrome
Patients with type 2 diabetes or metabolic syndrome did not benefit from treatment with atorvastatin, when compared with patients without either metabolic disorder, according to a study published in the June 13 online Archives of Neurology.
Alfred Callahan, MD, from the Vanderbilt University School of Medicine in Nashville, and colleagues conducted a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial to determine whether the effect of treatment on the primary end point (risk for stroke) and secondary end points (occurrence of coronary and cardiovascular events and procedures) varied based on the presence of type 2 diabetes or metabolic syndrome.
“The SPARCL trial found that statin treatment reduced stroke risk in patients with recent stroke or TIA and no known coronary heart disease (CHD),” Dr. Callahan’s group wrote. “No information is available, however, on the effect of statins on secondary stroke prevention in diabetic patients or in those with metabolic syndrome.”
Of the 4,731 subjects enrolled in the trial, 794 had diabetes and 642 had metabolic syndrome; 3,295 had neither condition and were included as the reference group. All patients were adults who had an ischemic or hemorrhagic stroke or TIA one to six months prior to randomization.
“The risk of stroke was 11.0% in the reference group, 18.1% in subjects with type 2 diabetes, and 10.7% in those with metabolic syndrome,” the investigators reported. “Subjects with type 2 diabetes mellitus were more likely to have any of the primary and secondary end points, including death.” Patients with metabolic syndrome had no increase in the risk of major cardiovascular events or major coronary events, but they were more likely to have any CHD event or revascularization procedure.
“In this post hoc analysis, we found that SPARCL subjects with type 2 diabetes mellitus were at higher risk for recurrent stroke and cardiovascular events but that there was no difference in the effect of statin treatment in reducing these events in subjects with or without type 2 diabetes or metabolic syndrome,” the authors concluded. They also noted that the possibility of variation on the benefit of statin treatment in subjects with or without type 2 diabetes or metabolic syndrome cannot be excluded by their analysis.
Callahan A, Amarenco P, Goldstein LB, et al. Risk of stroke and cardiovascular events after ischemic stroke or transient ischemic attack in patients with type 2 diabetes or metabolic syndrome: Secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Arch Neurol. 2011 Jun 13; [Epub ahead of print].

Does Stress Increase the Risk for Multiple Sclerosis?
Daily life- and work-related stress and childhood trauma have no significant impact on increasing the risk of developing multiple sclerosis (MS), according to a study published in the May 31 issue of Neurology.
“Several studies have shown that stressful life events are associated with a subsequent significant increase in risk of MS exacerbations,” the authors wrote. “We wanted to study prospectively whether stress can increase the risk of developing the disease itself.”
Trond Riise, PhD, from the Department of Public Health and Primary Health Care at the University of Bergen in Norway, and colleagues analyzed questionnaires regarding stress at work and home and the effects of physical and sexual abuse in childhood and adolescence completed by women in the Nurses’ Health Study and Nurses’ Health Study II who developed MS during the study period. They then conducted separate analyses by levels of stress and by severity of childhood abuse to calculate incidence rates and hazard ratios of MS.
“Stress measurements were available for 77 of the 94 women who had developed MS,” the researchers reported. “Adjusting for age, ethnicity, latitude at birth, BMI at age 18, and biannually updated smoking status, there were no significant differences in the risk of MS between any of the levels of stress at home or at work.” Of the 292 women from the Nurses’ Health Study II who responded to questions about childhood trauma, 7% reported severe abuse; there was no significant increased risk.
The lack of a significant relationship between stress and trauma and the risk for MS could potentially be caused by the study’s retrospective design. “A major challenge when studying this relation is to achieve unbiased measurement of stress,” the authors explained. “The possibility that these assessments were not sensitive to the stressors and stress mechanisms that might increase risk of developing MS cannot be ruled out.
“These results do not support a major role of stress [for developing MS], but repeated and more focused measures of stress are needed to firmly exclude stress as a potential risk factor for MS,” the investigators concluded.
Riise T, Mohr DC, Munger KL, et al. Stress and the risk of multiple sclerosis. Neurology. 2011;76(22);1866-1871.