Multiple Sclerosis

Neurologic and psychiatric comorbidities pose additional challenges for treating patients with MS.

HONOLULU—A survey comparing adults with multiple sclerosis (MS) and healthy controls revealed that persons with the disease have a higher prevalence of comorbid neurologic, psychiatric, and cardiovascular symptoms and conditions, all of which may complicate disease management. The research was presented at the 63rd Annual Meeting of the American Academy of Neurology.

“A better understanding of the nature and prevalence of comorbid illness in MS may guide development of treatment protocols to improve outcomes in individuals with MS with comorbidities,” reported Michelle Stewart, PhD, from Pfizer Global Research and Development in New London, Connecticut, and colleagues.

The researchers collected data from the National Health and Wellness Survey, an internet-based annual study of health care attitudes in the United States. Dr. Stewart’s group analyzed responses from 549 patients with MS (mean age, 48.6) and 74,451 healthy controls (mean age, 47.9). Respondents’ demographics, health status information, and comorbid symptoms and conditions were recorded.

“Compared with controls, a greater proportion of individuals with MS reported being female and white,” the researchers reported. Although patients with MS were more likely to be poor and unemployed, they were also more likely to have health insurance. Regarding health status, “individuals with MS were less likely to use alcohol, less likely to exercise, and more likely to smoke.”

Common Neurologic, Psychiatric, and Cardiovascular Comorbidities
When the researchers compared data from patients with MS and healthy controls, they found statistically significant differences for several neurologic, psychiatric, and cardiovascular symptoms and conditions.

Pain, headache, migraine, restless legs syndrome, stroke, epilepsy, dementia, Parkinson’s disease, and Alzheimer’s disease were all more prevalent in patients with MS than in persons without the disorder. More than 50% of the MS cohort reported pain and headache as neurologic symptoms; Parkinson’s disease (2.0%) and Alzheimer’s disease (1.9%) were the least commonly reported conditions.

Among psychiatric comorbidities that were recorded, sleep difficulties, depression, and anxiety were the most commonly reported symptoms in both populations. Statistically significant differences were also found between patients with MS and controls in the following conditions and symptoms: insomnia, panic disorder, bipolar disorder, generalized anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder, and narcolepsy.

Patients with MS had a higher prevalence of cardiovascular symptoms, including angina, arrhythmia, transient ischemic stroke, and deep vein thrombosis, compared with controls. However, the investigators reported, “rates for hypertension, high cholesterol, ever had a heart attack, congestive heart failure, and atrial fibrillation were similar for individuals with and without MS.”

Impact of Comorbid Illness on MS Treatment
“An increasing amount of evidence suggests that physical and mental comorbidities, and adverse health factors such as smoking and obesity, are common in MS,” the authors stated. “These comorbidities and lifestyle factors may affect the diagnostic delay between symptom onset and diagnosis, disability progression, and health-related quality of life.”

In this study, persons with MS had significant comorbid illness, compared with controls, as the researchers expected. “Neurologic and psychiatric comorbid conditions and symptoms are common and typically more prevalent in MS,” the authors explained. “Cardiovascular risk factors in individuals with MS are similar to risk factors in controls, although some conditions have a higher association.

“The presence of comorbidities in individuals with MS merits attention as they may present challenges in managing this chronic and progressive disorder,” the researchers concluded.

Neurologic and psychiatric comorbidities pose additional challenges for treating patients with MS.

HONOLULU—A survey comparing adults with multiple sclerosis (MS) and healthy controls revealed that persons with the disease have a higher prevalence of comorbid neurologic, psychiatric, and cardiovascular symptoms and conditions, all of which may complicate disease management. The research was presented at the 63rd Annual Meeting of the American Academy of Neurology.

“A better understanding of the nature and prevalence of comorbid illness in MS may guide development of treatment protocols to improve outcomes in individuals with MS with comorbidities,” reported Michelle Stewart, PhD, from Pfizer Global Research and Development in New London, Connecticut, and colleagues.

The researchers collected data from the National Health and Wellness Survey, an internet-based annual study of health care attitudes in the United States. Dr. Stewart’s group analyzed responses from 549 patients with MS (mean age, 48.6) and 74,451 healthy controls (mean age, 47.9). Respondents’ demographics, health status information, and comorbid symptoms and conditions were recorded.

“Compared with controls, a greater proportion of individuals with MS reported being female and white,” the researchers reported. Although patients with MS were more likely to be poor and unemployed, they were also more likely to have health insurance. Regarding health status, “individuals with MS were less likely to use alcohol, less likely to exercise, and more likely to smoke.”

Common Neurologic, Psychiatric, and Cardiovascular Comorbidities
When the researchers compared data from patients with MS and healthy controls, they found statistically significant differences for several neurologic, psychiatric, and cardiovascular symptoms and conditions.

Pain, headache, migraine, restless legs syndrome, stroke, epilepsy, dementia, Parkinson’s disease, and Alzheimer’s disease were all more prevalent in patients with MS than in persons without the disorder. More than 50% of the MS cohort reported pain and headache as neurologic symptoms; Parkinson’s disease (2.0%) and Alzheimer’s disease (1.9%) were the least commonly reported conditions.

Among psychiatric comorbidities that were recorded, sleep difficulties, depression, and anxiety were the most commonly reported symptoms in both populations. Statistically significant differences were also found between patients with MS and controls in the following conditions and symptoms: insomnia, panic disorder, bipolar disorder, generalized anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder, and narcolepsy.

Patients with MS had a higher prevalence of cardiovascular symptoms, including angina, arrhythmia, transient ischemic stroke, and deep vein thrombosis, compared with controls. However, the investigators reported, “rates for hypertension, high cholesterol, ever had a heart attack, congestive heart failure, and atrial fibrillation were similar for individuals with and without MS.”

Impact of Comorbid Illness on MS Treatment
“An increasing amount of evidence suggests that physical and mental comorbidities, and adverse health factors such as smoking and obesity, are common in MS,” the authors stated. “These comorbidities and lifestyle factors may affect the diagnostic delay between symptom onset and diagnosis, disability progression, and health-related quality of life.”

In this study, persons with MS had significant comorbid illness, compared with controls, as the researchers expected. “Neurologic and psychiatric comorbid conditions and symptoms are common and typically more prevalent in MS,” the authors explained. “Cardiovascular risk factors in individuals with MS are similar to risk factors in controls, although some conditions have a higher association.

“The presence of comorbidities in individuals with MS merits attention as they may present challenges in managing this chronic and progressive disorder,” the researchers concluded.

Neurologic and psychiatric comorbidities pose additional challenges for treating patients with MS.

HONOLULU—A survey comparing adults with multiple sclerosis (MS) and healthy controls revealed that persons with the disease have a higher prevalence of comorbid neurologic, psychiatric, and cardiovascular symptoms and conditions, all of which may complicate disease management. The research was presented at the 63rd Annual Meeting of the American Academy of Neurology.

“A better understanding of the nature and prevalence of comorbid illness in MS may guide development of treatment protocols to improve outcomes in individuals with MS with comorbidities,” reported Michelle Stewart, PhD, from Pfizer Global Research and Development in New London, Connecticut, and colleagues.

The researchers collected data from the National Health and Wellness Survey, an internet-based annual study of health care attitudes in the United States. Dr. Stewart’s group analyzed responses from 549 patients with MS (mean age, 48.6) and 74,451 healthy controls (mean age, 47.9). Respondents’ demographics, health status information, and comorbid symptoms and conditions were recorded.

“Compared with controls, a greater proportion of individuals with MS reported being female and white,” the researchers reported. Although patients with MS were more likely to be poor and unemployed, they were also more likely to have health insurance. Regarding health status, “individuals with MS were less likely to use alcohol, less likely to exercise, and more likely to smoke.”

Common Neurologic, Psychiatric, and Cardiovascular Comorbidities
When the researchers compared data from patients with MS and healthy controls, they found statistically significant differences for several neurologic, psychiatric, and cardiovascular symptoms and conditions.

Pain, headache, migraine, restless legs syndrome, stroke, epilepsy, dementia, Parkinson’s disease, and Alzheimer’s disease were all more prevalent in patients with MS than in persons without the disorder. More than 50% of the MS cohort reported pain and headache as neurologic symptoms; Parkinson’s disease (2.0%) and Alzheimer’s disease (1.9%) were the least commonly reported conditions.

Among psychiatric comorbidities that were recorded, sleep difficulties, depression, and anxiety were the most commonly reported symptoms in both populations. Statistically significant differences were also found between patients with MS and controls in the following conditions and symptoms: insomnia, panic disorder, bipolar disorder, generalized anxiety disorder, obsessive compulsive disorder, posttraumatic stress disorder, and narcolepsy.

Patients with MS had a higher prevalence of cardiovascular symptoms, including angina, arrhythmia, transient ischemic stroke, and deep vein thrombosis, compared with controls. However, the investigators reported, “rates for hypertension, high cholesterol, ever had a heart attack, congestive heart failure, and atrial fibrillation were similar for individuals with and without MS.”

Impact of Comorbid Illness on MS Treatment
“An increasing amount of evidence suggests that physical and mental comorbidities, and adverse health factors such as smoking and obesity, are common in MS,” the authors stated. “These comorbidities and lifestyle factors may affect the diagnostic delay between symptom onset and diagnosis, disability progression, and health-related quality of life.”

In this study, persons with MS had significant comorbid illness, compared with controls, as the researchers expected. “Neurologic and psychiatric comorbid conditions and symptoms are common and typically more prevalent in MS,” the authors explained. “Cardiovascular risk factors in individuals with MS are similar to risk factors in controls, although some conditions have a higher association.

“The presence of comorbidities in individuals with MS merits attention as they may present challenges in managing this chronic and progressive disorder,” the researchers concluded.

One third of patients with pathologically confirmed early-onset Alzheimer’s disease presented with atypical symptoms, and 53% of patients with nonamnestic presentations were initially misdiagnosed, according to a study in the May 17 Neurology. Researchers conducted a retrospective review of clinical data from patients with confirmed early-onset Alzheimer’s disease to determine the frequency and types of incorrect diagnoses. The majority of these cases were diagnosed with other types of dementia, including pseudodementia with depression, semantic dementia, and primary progressive aphasia. “Early-onset Alzheimer’s disease diagnosis often represents a challenge because of the high frequency of atypical presentations,” the study authors wrote. More than one-third (37.5%) of patients presented with atypical symptoms other than memory problems; the most prevalent of these was behavioral/executive dysfunction.

Neuronal activity may be a potential mechanism for vulnerability to amyloid-β deposition in certain areas of the brain, researchers reported in the May 1 online Nature Neuroscience. The investigators examined endogenous neuronal activity in mice with Alzheimer’s disease and determined that this activity regulates the regional concentration of interstitial fluid amyloid-β, which drives local aggregation of amyloid-β. Using unilateral vibrissal stimulation in the contralateral barrel cortex, they found that activity increased interstitial fluid amyloid-β. Unilateral vibrissal deprivation decreased interstitial fluid amyloid-β deposition; long-term deprivation also decreased amyloid plaque formation and growth. “Our results suggest a mechanism to account for the vulnerability of specific brain regions to amyloid-β deposition in Alzheimer’s disease,” the authors concluded.

A newly confirmed genetic risk allele of the clusterin gene contributes to white matter degeneration in young adults and may increase the risk for Alzheimer’s disease later in life, according to results published in the May 4 Journal of Neuroscience. Investigators used diffusion-tensor MRI to scan the brains of 398 healthy young adults (mean age, 23.6) and to evaluate whether the C-allele clusterin risk variant was associated with lower white matter integrity. “Each C-allele copy of the clusterin variant was associated with lower fractional anisotropy—a widely accepted measure of white matter integrity—in multiple brain regions,” the authors wrote. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. “Young healthy carriers of the clusterin gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing Alzheimer’s disease later in life,” the researchers concluded.

A higher BMI may improve survival in patients with amyotrophic lateral sclerosis (ALS). As published in the May 23 online Muscle & Nerve, investigators aimed to determine whether cholesterol levels are an independent predictor of ALS survival. They measured cholesterol levels in 427 people with ALS from three clinical trial databases and found that the low-density and high-density lipoprotein level ratio did not decrease over time, even though BMI significantly declined. “After adjusting for BMI, forced vital capacity, and age, the lipid ratio was not associated with survival,” the investigators wrote. The highest survival rate, though, was found among patients with a BMI between 30 and 35, or mild obesity. “We found that dyslipidemia is not an independent predictor of survival in ALS,” the researchers concluded, whereas, “BMI is an independent prognostic factor for survival after adjusting for markers of disease severity.”

Patients with a history of intracerebral hemorrhage (ICH) should avoid using statins for prevention of ischemic cardiac and cerebrovascular disease, according to a study in the May Archives of Neurology. Statins are widely prescribed for disease prevention, the authors noted, and “although serious adverse effects are uncommon, results from a recent clinical trial suggested increased risk of ICH associated with statin use.” To determine if statin therapy should be avoided in patients with a baseline elevated risk of ICH, investigators evaluated the risks and benefits of the therapy in patients with prior ICH using clinical parameters such as hemorrhage location (deep or lobar). For survivors of ICH both with and without prior cardiovascular events, the benefits of statin therapy were not strong enough to offset the increased risk for hemorrhage recurrence.

Adverse changes in sleep duration are associated with poorer cognitive function in middle-aged adults, per a study in the May 1 Sleep. Researchers conducted cross-sectional studies of women and men (age range, 45 to 69) to examine the effect of changes in sleep duration on cognitive function. Participants’ cognitive function was assessed at baseline, and their sleep duration on an average weeknight was measured once at baseline and again an average of 5.4 years later. After adjustment for age, gender, education, and occupation, the authors reported that “firm evidence remained for an association between an increase from seven or eight hours sleep and lower cognitive function for all tests, except memory, and between a decrease from six or eight hours sleep and poorer reasoning, vocabulary, and Mini-Mental State Examination score.” These adverse changes in duration were equivalent to a four- to seven-year increase in age.

African Americans with multiple sclerosis (MS) have lower vitamin D levels than their healthy counterparts, according to a study published in the May 24 Neurology. Researchers conducted a cross-sectional study of 339 African-American patients with MS and 342 without MS to determine if vitamin D levels were associated with MS disease severity. Between 71% and 77% of all participants were vitamin D–deficient and 93% to 94% were vitamin D–insufficient, the authors reported. Overall, vitamin D levels were lower in patients with MS, but this was due to differences in climate and geography and did not have an impact on disease severity. “These results are consistent with observations in other populations that lower [vitamin D level] is associated with having MS,” the investigators concluded, “but also highlight the importance of climate and ancestry in determining vitamin D status.”

Protein-based human-induced pluripotent stem cells (hiPSCs) and those derived from human embryonic stem cells (hESCs) may be effective in the treatment of Parkinson’s disease, according to a study in the May 16 Journal of Clinical Investigation. Results showed that neuronal precursors cells derived from hESCs and protein-based hiPSCs reversed disease when transplanted into the brains of rats modeling Parkinson’s disease. The researchers attempted to use neuronal cells derived from virus-based hiPSCs but were unable to do so because these virus-based cells exhibited apoptotic cell death. “[hiPSCs] are a potentially unlimited source of patient-specific cells for transplantation…. These data support the clinical potential of protein-based hiPSCs for personalized cell therapy of Parkinson’s disease,” the investigators concluded.

Women may have a greater risk than men for adverse events following certain stroke prevention procedures, as reported in the May 6 online Lancet Neurology. A total of 2,502 patients with symptomatic and asymptomatic stenosis were randomized to undergo carotid endarterectomy or carotid artery stenting. The rates of periprocedural stroke, myocardial infarction, and death were similar in men who underwent endarterectomy (4.9%) and stenting (4.3%). In women, however, a significant difference in rates of adverse events was observed—3.8% for endarterectomy versus 6.8% for stenting. “Periprocedural risk of events seems to be higher in women who have carotid artery stenting than those who have carotid endarterectomy, whereas there is little difference in men,” the authors concluded. “Additional data are needed to confirm whether this differential risk should be taken into account in decisions for treatment of carotid disease in women.”

About 14% of ischemic strokes presented at emergency departments are wake-up strokes, researchers reported in the May 10 Neurology. Wake-up strokes, according to the authors, cannot be distinguished from other types of stroke based on clinical features or outcome, making them difficult to treat with effective clot-busting therapies. The researchers analyzed data from patients presenting at emergency departments with ischemic stroke; they identified 1,854 ischemic stroke cases, 273 of which were wake-up strokes. “There were no differences between wake-up strokes and all other strokes with regard to clinical features or outcomes except for minor differences in age and baseline retrospective NIH Stroke Scale score,” the authors reported. “Of the wake-up strokes, at least 98 (35.9%) would have been eligible for thrombolysis if arrival time were not a factor.”

The annual rate of coronary artery bypass graft surgeries decreased 30% between 2001 and 2008, while rates of other percutaneous coronary interventions remained stable, according to an examination of national trends published in the May 4 JAMA. Investigators conducted a serial cross-sectional study to examine time trends of patients undergoing revascularization procedures, and determined that the annual surgery rate decreased from 1,742 to 1,081 per million adults in 2008. “Between 2001 and 2008, the number of hospitals … providing [coronary artery bypass graft surgery] increased by 12%, and the number of [percutaneous coronary interventions] hospitals increased by 26%,” the authors reported. They noted that new revascularization technologies, new clinical evidence from trials, and updated clinical guidelines may have affected the volume and distribution of coronary revascularizations.

Patients with traumatic brain injury (TBI) and refractory intracranial hypertension may benefit from decompressive craniectomy, but they may also experience unfavorable outcomes, according to a study in the April 21 New England Journal of Medicine. Researchers randomly assigned 155 adults with TBI and intracranial hypertension to undergo either bifrontotemporoparietal decompressive craniectomy or standard care. The results revealed that the standard-care group had higher levels of intracranial pressure and longer stays in the intensive care unit. “However, patients undergoing craniectomy had worse scores on the Extended Glasgow Outcome Scale than those receiving standard care,” the authors noted. Patients with craniectomy were also more than twice as likely to experience an unfavorable outcome, including death, vegetative state, or severe disability.

One third of patients with pathologically confirmed early-onset Alzheimer’s disease presented with atypical symptoms, and 53% of patients with nonamnestic presentations were initially misdiagnosed, according to a study in the May 17 Neurology. Researchers conducted a retrospective review of clinical data from patients with confirmed early-onset Alzheimer’s disease to determine the frequency and types of incorrect diagnoses. The majority of these cases were diagnosed with other types of dementia, including pseudodementia with depression, semantic dementia, and primary progressive aphasia. “Early-onset Alzheimer’s disease diagnosis often represents a challenge because of the high frequency of atypical presentations,” the study authors wrote. More than one-third (37.5%) of patients presented with atypical symptoms other than memory problems; the most prevalent of these was behavioral/executive dysfunction.

Neuronal activity may be a potential mechanism for vulnerability to amyloid-β deposition in certain areas of the brain, researchers reported in the May 1 online Nature Neuroscience. The investigators examined endogenous neuronal activity in mice with Alzheimer’s disease and determined that this activity regulates the regional concentration of interstitial fluid amyloid-β, which drives local aggregation of amyloid-β. Using unilateral vibrissal stimulation in the contralateral barrel cortex, they found that activity increased interstitial fluid amyloid-β. Unilateral vibrissal deprivation decreased interstitial fluid amyloid-β deposition; long-term deprivation also decreased amyloid plaque formation and growth. “Our results suggest a mechanism to account for the vulnerability of specific brain regions to amyloid-β deposition in Alzheimer’s disease,” the authors concluded.

A newly confirmed genetic risk allele of the clusterin gene contributes to white matter degeneration in young adults and may increase the risk for Alzheimer’s disease later in life, according to results published in the May 4 Journal of Neuroscience. Investigators used diffusion-tensor MRI to scan the brains of 398 healthy young adults (mean age, 23.6) and to evaluate whether the C-allele clusterin risk variant was associated with lower white matter integrity. “Each C-allele copy of the clusterin variant was associated with lower fractional anisotropy—a widely accepted measure of white matter integrity—in multiple brain regions,” the authors wrote. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. “Young healthy carriers of the clusterin gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing Alzheimer’s disease later in life,” the researchers concluded.

A higher BMI may improve survival in patients with amyotrophic lateral sclerosis (ALS). As published in the May 23 online Muscle & Nerve, investigators aimed to determine whether cholesterol levels are an independent predictor of ALS survival. They measured cholesterol levels in 427 people with ALS from three clinical trial databases and found that the low-density and high-density lipoprotein level ratio did not decrease over time, even though BMI significantly declined. “After adjusting for BMI, forced vital capacity, and age, the lipid ratio was not associated with survival,” the investigators wrote. The highest survival rate, though, was found among patients with a BMI between 30 and 35, or mild obesity. “We found that dyslipidemia is not an independent predictor of survival in ALS,” the researchers concluded, whereas, “BMI is an independent prognostic factor for survival after adjusting for markers of disease severity.”

Patients with a history of intracerebral hemorrhage (ICH) should avoid using statins for prevention of ischemic cardiac and cerebrovascular disease, according to a study in the May Archives of Neurology. Statins are widely prescribed for disease prevention, the authors noted, and “although serious adverse effects are uncommon, results from a recent clinical trial suggested increased risk of ICH associated with statin use.” To determine if statin therapy should be avoided in patients with a baseline elevated risk of ICH, investigators evaluated the risks and benefits of the therapy in patients with prior ICH using clinical parameters such as hemorrhage location (deep or lobar). For survivors of ICH both with and without prior cardiovascular events, the benefits of statin therapy were not strong enough to offset the increased risk for hemorrhage recurrence.

Adverse changes in sleep duration are associated with poorer cognitive function in middle-aged adults, per a study in the May 1 Sleep. Researchers conducted cross-sectional studies of women and men (age range, 45 to 69) to examine the effect of changes in sleep duration on cognitive function. Participants’ cognitive function was assessed at baseline, and their sleep duration on an average weeknight was measured once at baseline and again an average of 5.4 years later. After adjustment for age, gender, education, and occupation, the authors reported that “firm evidence remained for an association between an increase from seven or eight hours sleep and lower cognitive function for all tests, except memory, and between a decrease from six or eight hours sleep and poorer reasoning, vocabulary, and Mini-Mental State Examination score.” These adverse changes in duration were equivalent to a four- to seven-year increase in age.

African Americans with multiple sclerosis (MS) have lower vitamin D levels than their healthy counterparts, according to a study published in the May 24 Neurology. Researchers conducted a cross-sectional study of 339 African-American patients with MS and 342 without MS to determine if vitamin D levels were associated with MS disease severity. Between 71% and 77% of all participants were vitamin D–deficient and 93% to 94% were vitamin D–insufficient, the authors reported. Overall, vitamin D levels were lower in patients with MS, but this was due to differences in climate and geography and did not have an impact on disease severity. “These results are consistent with observations in other populations that lower [vitamin D level] is associated with having MS,” the investigators concluded, “but also highlight the importance of climate and ancestry in determining vitamin D status.”

Protein-based human-induced pluripotent stem cells (hiPSCs) and those derived from human embryonic stem cells (hESCs) may be effective in the treatment of Parkinson’s disease, according to a study in the May 16 Journal of Clinical Investigation. Results showed that neuronal precursors cells derived from hESCs and protein-based hiPSCs reversed disease when transplanted into the brains of rats modeling Parkinson’s disease. The researchers attempted to use neuronal cells derived from virus-based hiPSCs but were unable to do so because these virus-based cells exhibited apoptotic cell death. “[hiPSCs] are a potentially unlimited source of patient-specific cells for transplantation…. These data support the clinical potential of protein-based hiPSCs for personalized cell therapy of Parkinson’s disease,” the investigators concluded.

Women may have a greater risk than men for adverse events following certain stroke prevention procedures, as reported in the May 6 online Lancet Neurology. A total of 2,502 patients with symptomatic and asymptomatic stenosis were randomized to undergo carotid endarterectomy or carotid artery stenting. The rates of periprocedural stroke, myocardial infarction, and death were similar in men who underwent endarterectomy (4.9%) and stenting (4.3%). In women, however, a significant difference in rates of adverse events was observed—3.8% for endarterectomy versus 6.8% for stenting. “Periprocedural risk of events seems to be higher in women who have carotid artery stenting than those who have carotid endarterectomy, whereas there is little difference in men,” the authors concluded. “Additional data are needed to confirm whether this differential risk should be taken into account in decisions for treatment of carotid disease in women.”

About 14% of ischemic strokes presented at emergency departments are wake-up strokes, researchers reported in the May 10 Neurology. Wake-up strokes, according to the authors, cannot be distinguished from other types of stroke based on clinical features or outcome, making them difficult to treat with effective clot-busting therapies. The researchers analyzed data from patients presenting at emergency departments with ischemic stroke; they identified 1,854 ischemic stroke cases, 273 of which were wake-up strokes. “There were no differences between wake-up strokes and all other strokes with regard to clinical features or outcomes except for minor differences in age and baseline retrospective NIH Stroke Scale score,” the authors reported. “Of the wake-up strokes, at least 98 (35.9%) would have been eligible for thrombolysis if arrival time were not a factor.”

The annual rate of coronary artery bypass graft surgeries decreased 30% between 2001 and 2008, while rates of other percutaneous coronary interventions remained stable, according to an examination of national trends published in the May 4 JAMA. Investigators conducted a serial cross-sectional study to examine time trends of patients undergoing revascularization procedures, and determined that the annual surgery rate decreased from 1,742 to 1,081 per million adults in 2008. “Between 2001 and 2008, the number of hospitals … providing [coronary artery bypass graft surgery] increased by 12%, and the number of [percutaneous coronary interventions] hospitals increased by 26%,” the authors reported. They noted that new revascularization technologies, new clinical evidence from trials, and updated clinical guidelines may have affected the volume and distribution of coronary revascularizations.

Patients with traumatic brain injury (TBI) and refractory intracranial hypertension may benefit from decompressive craniectomy, but they may also experience unfavorable outcomes, according to a study in the April 21 New England Journal of Medicine. Researchers randomly assigned 155 adults with TBI and intracranial hypertension to undergo either bifrontotemporoparietal decompressive craniectomy or standard care. The results revealed that the standard-care group had higher levels of intracranial pressure and longer stays in the intensive care unit. “However, patients undergoing craniectomy had worse scores on the Extended Glasgow Outcome Scale than those receiving standard care,” the authors noted. Patients with craniectomy were also more than twice as likely to experience an unfavorable outcome, including death, vegetative state, or severe disability.

One third of patients with pathologically confirmed early-onset Alzheimer’s disease presented with atypical symptoms, and 53% of patients with nonamnestic presentations were initially misdiagnosed, according to a study in the May 17 Neurology. Researchers conducted a retrospective review of clinical data from patients with confirmed early-onset Alzheimer’s disease to determine the frequency and types of incorrect diagnoses. The majority of these cases were diagnosed with other types of dementia, including pseudodementia with depression, semantic dementia, and primary progressive aphasia. “Early-onset Alzheimer’s disease diagnosis often represents a challenge because of the high frequency of atypical presentations,” the study authors wrote. More than one-third (37.5%) of patients presented with atypical symptoms other than memory problems; the most prevalent of these was behavioral/executive dysfunction.

Neuronal activity may be a potential mechanism for vulnerability to amyloid-β deposition in certain areas of the brain, researchers reported in the May 1 online Nature Neuroscience. The investigators examined endogenous neuronal activity in mice with Alzheimer’s disease and determined that this activity regulates the regional concentration of interstitial fluid amyloid-β, which drives local aggregation of amyloid-β. Using unilateral vibrissal stimulation in the contralateral barrel cortex, they found that activity increased interstitial fluid amyloid-β. Unilateral vibrissal deprivation decreased interstitial fluid amyloid-β deposition; long-term deprivation also decreased amyloid plaque formation and growth. “Our results suggest a mechanism to account for the vulnerability of specific brain regions to amyloid-β deposition in Alzheimer’s disease,” the authors concluded.

A newly confirmed genetic risk allele of the clusterin gene contributes to white matter degeneration in young adults and may increase the risk for Alzheimer’s disease later in life, according to results published in the May 4 Journal of Neuroscience. Investigators used diffusion-tensor MRI to scan the brains of 398 healthy young adults (mean age, 23.6) and to evaluate whether the C-allele clusterin risk variant was associated with lower white matter integrity. “Each C-allele copy of the clusterin variant was associated with lower fractional anisotropy—a widely accepted measure of white matter integrity—in multiple brain regions,” the authors wrote. These regions included the splenium of the corpus callosum, the fornix, cingulum, and superior and inferior longitudinal fasciculi in both brain hemispheres. “Young healthy carriers of the clusterin gene risk variant showed a distinct profile of lower white matter integrity that may increase vulnerability to developing Alzheimer’s disease later in life,” the researchers concluded.

A higher BMI may improve survival in patients with amyotrophic lateral sclerosis (ALS). As published in the May 23 online Muscle & Nerve, investigators aimed to determine whether cholesterol levels are an independent predictor of ALS survival. They measured cholesterol levels in 427 people with ALS from three clinical trial databases and found that the low-density and high-density lipoprotein level ratio did not decrease over time, even though BMI significantly declined. “After adjusting for BMI, forced vital capacity, and age, the lipid ratio was not associated with survival,” the investigators wrote. The highest survival rate, though, was found among patients with a BMI between 30 and 35, or mild obesity. “We found that dyslipidemia is not an independent predictor of survival in ALS,” the researchers concluded, whereas, “BMI is an independent prognostic factor for survival after adjusting for markers of disease severity.”

Patients with a history of intracerebral hemorrhage (ICH) should avoid using statins for prevention of ischemic cardiac and cerebrovascular disease, according to a study in the May Archives of Neurology. Statins are widely prescribed for disease prevention, the authors noted, and “although serious adverse effects are uncommon, results from a recent clinical trial suggested increased risk of ICH associated with statin use.” To determine if statin therapy should be avoided in patients with a baseline elevated risk of ICH, investigators evaluated the risks and benefits of the therapy in patients with prior ICH using clinical parameters such as hemorrhage location (deep or lobar). For survivors of ICH both with and without prior cardiovascular events, the benefits of statin therapy were not strong enough to offset the increased risk for hemorrhage recurrence.

Adverse changes in sleep duration are associated with poorer cognitive function in middle-aged adults, per a study in the May 1 Sleep. Researchers conducted cross-sectional studies of women and men (age range, 45 to 69) to examine the effect of changes in sleep duration on cognitive function. Participants’ cognitive function was assessed at baseline, and their sleep duration on an average weeknight was measured once at baseline and again an average of 5.4 years later. After adjustment for age, gender, education, and occupation, the authors reported that “firm evidence remained for an association between an increase from seven or eight hours sleep and lower cognitive function for all tests, except memory, and between a decrease from six or eight hours sleep and poorer reasoning, vocabulary, and Mini-Mental State Examination score.” These adverse changes in duration were equivalent to a four- to seven-year increase in age.

African Americans with multiple sclerosis (MS) have lower vitamin D levels than their healthy counterparts, according to a study published in the May 24 Neurology. Researchers conducted a cross-sectional study of 339 African-American patients with MS and 342 without MS to determine if vitamin D levels were associated with MS disease severity. Between 71% and 77% of all participants were vitamin D–deficient and 93% to 94% were vitamin D–insufficient, the authors reported. Overall, vitamin D levels were lower in patients with MS, but this was due to differences in climate and geography and did not have an impact on disease severity. “These results are consistent with observations in other populations that lower [vitamin D level] is associated with having MS,” the investigators concluded, “but also highlight the importance of climate and ancestry in determining vitamin D status.”

Protein-based human-induced pluripotent stem cells (hiPSCs) and those derived from human embryonic stem cells (hESCs) may be effective in the treatment of Parkinson’s disease, according to a study in the May 16 Journal of Clinical Investigation. Results showed that neuronal precursors cells derived from hESCs and protein-based hiPSCs reversed disease when transplanted into the brains of rats modeling Parkinson’s disease. The researchers attempted to use neuronal cells derived from virus-based hiPSCs but were unable to do so because these virus-based cells exhibited apoptotic cell death. “[hiPSCs] are a potentially unlimited source of patient-specific cells for transplantation…. These data support the clinical potential of protein-based hiPSCs for personalized cell therapy of Parkinson’s disease,” the investigators concluded.

Women may have a greater risk than men for adverse events following certain stroke prevention procedures, as reported in the May 6 online Lancet Neurology. A total of 2,502 patients with symptomatic and asymptomatic stenosis were randomized to undergo carotid endarterectomy or carotid artery stenting. The rates of periprocedural stroke, myocardial infarction, and death were similar in men who underwent endarterectomy (4.9%) and stenting (4.3%). In women, however, a significant difference in rates of adverse events was observed—3.8% for endarterectomy versus 6.8% for stenting. “Periprocedural risk of events seems to be higher in women who have carotid artery stenting than those who have carotid endarterectomy, whereas there is little difference in men,” the authors concluded. “Additional data are needed to confirm whether this differential risk should be taken into account in decisions for treatment of carotid disease in women.”

About 14% of ischemic strokes presented at emergency departments are wake-up strokes, researchers reported in the May 10 Neurology. Wake-up strokes, according to the authors, cannot be distinguished from other types of stroke based on clinical features or outcome, making them difficult to treat with effective clot-busting therapies. The researchers analyzed data from patients presenting at emergency departments with ischemic stroke; they identified 1,854 ischemic stroke cases, 273 of which were wake-up strokes. “There were no differences between wake-up strokes and all other strokes with regard to clinical features or outcomes except for minor differences in age and baseline retrospective NIH Stroke Scale score,” the authors reported. “Of the wake-up strokes, at least 98 (35.9%) would have been eligible for thrombolysis if arrival time were not a factor.”

The annual rate of coronary artery bypass graft surgeries decreased 30% between 2001 and 2008, while rates of other percutaneous coronary interventions remained stable, according to an examination of national trends published in the May 4 JAMA. Investigators conducted a serial cross-sectional study to examine time trends of patients undergoing revascularization procedures, and determined that the annual surgery rate decreased from 1,742 to 1,081 per million adults in 2008. “Between 2001 and 2008, the number of hospitals … providing [coronary artery bypass graft surgery] increased by 12%, and the number of [percutaneous coronary interventions] hospitals increased by 26%,” the authors reported. They noted that new revascularization technologies, new clinical evidence from trials, and updated clinical guidelines may have affected the volume and distribution of coronary revascularizations.

Patients with traumatic brain injury (TBI) and refractory intracranial hypertension may benefit from decompressive craniectomy, but they may also experience unfavorable outcomes, according to a study in the April 21 New England Journal of Medicine. Researchers randomly assigned 155 adults with TBI and intracranial hypertension to undergo either bifrontotemporoparietal decompressive craniectomy or standard care. The results revealed that the standard-care group had higher levels of intracranial pressure and longer stays in the intensive care unit. “However, patients undergoing craniectomy had worse scores on the Extended Glasgow Outcome Scale than those receiving standard care,” the authors noted. Patients with craniectomy were also more than twice as likely to experience an unfavorable outcome, including death, vegetative state, or severe disability.

HONOLULU – Ginkgo biloba and simvastatin were not helpful in patients with relapsing-remitting multiple sclerosis in separate randomized controlled trials.

Treatment with ginkgo at 120 mg twice a day for 12 weeks produced no significant, short-term improvements in cognitive function in a study of 121 patients. The addition of simvastatin (Zocor) to interferon therapy for multiple sclerosis in a separate study did not significantly reduce the annualized relapse rate after 1–3 years, investigators reported at the meeting.

In the first study, both the ginkgo and placebo groups had improved average scores on a battery of neuropsychological tests. There were no significant differences between groups in scores on the Paced Auditory Serial Addition Test, the California Verbal Learning Test II, the Controlled Oral Word Association Test, or the Stroop Color–Word Test, said Dr. Jesus Lovera of Louisiana State University, New Orleans.

The two groups also did not differ significantly in secondary outcomes (including perceived cognitive deficits, family reports of cognitive deficits, fatigue, or depression) or in rates of adverse events. In the ginkgo group, one patient had an MI and one developed a severe depressive episode requiring hospitalization, but these were not attributed to ginkgo.

While the study found no short-term cognitive benefits from ginkgo, it did not assess any potential long-term benefits, Dr. Lovera said. There are no approved treatments for impairment of cognition in people with multiple sclerosis, which affects 40%-50% of patients.

Dr. Per Soelberg Sørensen and his associates reported in a separate presentation on a study of 307 treatment-naive patients who were starting treatment with interferon-beta-1a (IFN-beta-1a, Avonex) for relapsing-remitting multiple sclerosis. They were randomized to add-on therapy with either placebo or 80 mg/day of simvastatin (40 mg/day in the first month) for 1–3 years. Patients were followed clinically every 3 months and brain MRIs were conducted at baseline and after 1 year of treatment. At least 1 year of follow-up was completed by 136 patients in the simvastatin group and 132 in the placebo group.

In the study, the annualized documented relapse rate was 31% higher in the simvastatin group (0.19) compared with the placebo group (0.14), but the difference was not statistically significant, said Dr. Sørensen of the Danish Multiple Sclerosis Center in the Rigshospitalet, Copenhagen.

The annualized total rate of documented and undocumented relapses was 15% higher in the simvastatin group (0.44), compared with the placebo group (0.38). Patients who received simvastatin had more new or enlarging T2 lesions on MRI than did those who received placebo (3 vs. 2.5). These and other measures were not statistically significant differences between groups, but suggested a trend toward more disease activity in the simvastatin group compared with placebo, Dr. Sørensen said.

Based on the findings of this multicenter study, simvastatin cannot be recommended as an add-on to IFN-beta-1a therapy for relapsing multiple sclerosis, but patients taking statins for treatment of hypercholesterolemia or to prevent cardiovascular disease should not be discouraged from taking them during IFN-beta-1a therapy, Dr. Sørensen said.

Dr. Lovera and two of his associates disclosed financial relationships with EMD Serono, Teva Pharmaceuticals, Biogen Idec, and/or Pfizer. The ginkgo and placebo were provided by Dr. Willmar Schwabe GmbH, Karlsruhe, Germany. The U.S. Department of Veterans Affairs funded his study.

Dr. Sørensen and multiple associates disclosed financial relationships with Biogen Idec, Merck Serono, Teva Neuroscience, Genmab, Novartis, Bayer Schering, and/or Sanofi-Aventis. The study was funded by Biogen Idec.

There was a trend toward more disease activity in the simvastatin group, compared with placebo.

Source DR. SØRENSEN

HONOLULU – Ginkgo biloba and simvastatin were not helpful in patients with relapsing-remitting multiple sclerosis in separate randomized controlled trials.

Treatment with ginkgo at 120 mg twice a day for 12 weeks produced no significant, short-term improvements in cognitive function in a study of 121 patients. The addition of simvastatin (Zocor) to interferon therapy for multiple sclerosis in a separate study did not significantly reduce the annualized relapse rate after 1–3 years, investigators reported at the meeting.

In the first study, both the ginkgo and placebo groups had improved average scores on a battery of neuropsychological tests. There were no significant differences between groups in scores on the Paced Auditory Serial Addition Test, the California Verbal Learning Test II, the Controlled Oral Word Association Test, or the Stroop Color–Word Test, said Dr. Jesus Lovera of Louisiana State University, New Orleans.

The two groups also did not differ significantly in secondary outcomes (including perceived cognitive deficits, family reports of cognitive deficits, fatigue, or depression) or in rates of adverse events. In the ginkgo group, one patient had an MI and one developed a severe depressive episode requiring hospitalization, but these were not attributed to ginkgo.

While the study found no short-term cognitive benefits from ginkgo, it did not assess any potential long-term benefits, Dr. Lovera said. There are no approved treatments for impairment of cognition in people with multiple sclerosis, which affects 40%-50% of patients.

Dr. Per Soelberg Sørensen and his associates reported in a separate presentation on a study of 307 treatment-naive patients who were starting treatment with interferon-beta-1a (IFN-beta-1a, Avonex) for relapsing-remitting multiple sclerosis. They were randomized to add-on therapy with either placebo or 80 mg/day of simvastatin (40 mg/day in the first month) for 1–3 years. Patients were followed clinically every 3 months and brain MRIs were conducted at baseline and after 1 year of treatment. At least 1 year of follow-up was completed by 136 patients in the simvastatin group and 132 in the placebo group.

In the study, the annualized documented relapse rate was 31% higher in the simvastatin group (0.19) compared with the placebo group (0.14), but the difference was not statistically significant, said Dr. Sørensen of the Danish Multiple Sclerosis Center in the Rigshospitalet, Copenhagen.

The annualized total rate of documented and undocumented relapses was 15% higher in the simvastatin group (0.44), compared with the placebo group (0.38). Patients who received simvastatin had more new or enlarging T2 lesions on MRI than did those who received placebo (3 vs. 2.5). These and other measures were not statistically significant differences between groups, but suggested a trend toward more disease activity in the simvastatin group compared with placebo, Dr. Sørensen said.

Based on the findings of this multicenter study, simvastatin cannot be recommended as an add-on to IFN-beta-1a therapy for relapsing multiple sclerosis, but patients taking statins for treatment of hypercholesterolemia or to prevent cardiovascular disease should not be discouraged from taking them during IFN-beta-1a therapy, Dr. Sørensen said.

Dr. Lovera and two of his associates disclosed financial relationships with EMD Serono, Teva Pharmaceuticals, Biogen Idec, and/or Pfizer. The ginkgo and placebo were provided by Dr. Willmar Schwabe GmbH, Karlsruhe, Germany. The U.S. Department of Veterans Affairs funded his study.

Dr. Sørensen and multiple associates disclosed financial relationships with Biogen Idec, Merck Serono, Teva Neuroscience, Genmab, Novartis, Bayer Schering, and/or Sanofi-Aventis. The study was funded by Biogen Idec.

There was a trend toward more disease activity in the simvastatin group, compared with placebo.

Source DR. SØRENSEN

HONOLULU – Ginkgo biloba and simvastatin were not helpful in patients with relapsing-remitting multiple sclerosis in separate randomized controlled trials.

Treatment with ginkgo at 120 mg twice a day for 12 weeks produced no significant, short-term improvements in cognitive function in a study of 121 patients. The addition of simvastatin (Zocor) to interferon therapy for multiple sclerosis in a separate study did not significantly reduce the annualized relapse rate after 1–3 years, investigators reported at the meeting.

In the first study, both the ginkgo and placebo groups had improved average scores on a battery of neuropsychological tests. There were no significant differences between groups in scores on the Paced Auditory Serial Addition Test, the California Verbal Learning Test II, the Controlled Oral Word Association Test, or the Stroop Color–Word Test, said Dr. Jesus Lovera of Louisiana State University, New Orleans.

The two groups also did not differ significantly in secondary outcomes (including perceived cognitive deficits, family reports of cognitive deficits, fatigue, or depression) or in rates of adverse events. In the ginkgo group, one patient had an MI and one developed a severe depressive episode requiring hospitalization, but these were not attributed to ginkgo.

While the study found no short-term cognitive benefits from ginkgo, it did not assess any potential long-term benefits, Dr. Lovera said. There are no approved treatments for impairment of cognition in people with multiple sclerosis, which affects 40%-50% of patients.

Dr. Per Soelberg Sørensen and his associates reported in a separate presentation on a study of 307 treatment-naive patients who were starting treatment with interferon-beta-1a (IFN-beta-1a, Avonex) for relapsing-remitting multiple sclerosis. They were randomized to add-on therapy with either placebo or 80 mg/day of simvastatin (40 mg/day in the first month) for 1–3 years. Patients were followed clinically every 3 months and brain MRIs were conducted at baseline and after 1 year of treatment. At least 1 year of follow-up was completed by 136 patients in the simvastatin group and 132 in the placebo group.

In the study, the annualized documented relapse rate was 31% higher in the simvastatin group (0.19) compared with the placebo group (0.14), but the difference was not statistically significant, said Dr. Sørensen of the Danish Multiple Sclerosis Center in the Rigshospitalet, Copenhagen.

The annualized total rate of documented and undocumented relapses was 15% higher in the simvastatin group (0.44), compared with the placebo group (0.38). Patients who received simvastatin had more new or enlarging T2 lesions on MRI than did those who received placebo (3 vs. 2.5). These and other measures were not statistically significant differences between groups, but suggested a trend toward more disease activity in the simvastatin group compared with placebo, Dr. Sørensen said.

Based on the findings of this multicenter study, simvastatin cannot be recommended as an add-on to IFN-beta-1a therapy for relapsing multiple sclerosis, but patients taking statins for treatment of hypercholesterolemia or to prevent cardiovascular disease should not be discouraged from taking them during IFN-beta-1a therapy, Dr. Sørensen said.

Dr. Lovera and two of his associates disclosed financial relationships with EMD Serono, Teva Pharmaceuticals, Biogen Idec, and/or Pfizer. The ginkgo and placebo were provided by Dr. Willmar Schwabe GmbH, Karlsruhe, Germany. The U.S. Department of Veterans Affairs funded his study.

Dr. Sørensen and multiple associates disclosed financial relationships with Biogen Idec, Merck Serono, Teva Neuroscience, Genmab, Novartis, Bayer Schering, and/or Sanofi-Aventis. The study was funded by Biogen Idec.

There was a trend toward more disease activity in the simvastatin group, compared with placebo.

Source DR. SØRENSEN

HONOLULU – Oral therapies for relapsing-remitting multiple sclerosis that are in development have neurologists feeling both excited and a bit apprehensive.

“There are a whole slew of orals coming,” Dr. Mariko Kita said in an interview at the meetingo “It's really exciting, but I think it will be challenging for the clinician” because there will be inadequate guidance on which drug or drugs to prioritize in treatment and how best to combine various therapies.

“I think it's going to be very intimidating, actually,” said Dr. Kita, director of the multiple sclerosis center at Virginia Mason Medical Center, Seattle.

She comoderated a session on multiple sclerosis trials that included a report on a pooled analysis of safety data on the only approved oral therapy for multiple sclerosis, fingolimod (Gilenya). (See story on p. 10.) The session also included positive phase III clinical trial results for the experimental oral therapy teriflunomide. Earlier in the meeting, separate investigators reported positive phase III clinical trial results for the experimental oral therapy laquinimod.

Another oral agent under study, BG-12 (dimethyl fumarate), received Fast Track designation from the Food and Drug Administration and is in phase III clinical trials. Cladribine (Leustatin), which is currently marketed as chemotherapy for certain leukemias and lymphomas, initially was rejected by the FDA when it was submitted for approval as an oral therapy for multiple sclerosis. Following resubmission by the manufacturer, the FDA in early 2011 sent a letter to the company acknowledging sufficient data on the drug's efficacy in multiple sclerosis but requiring more data on safety and risk-benefit considerations before it could be approved.

Dr. Kita's comoderator, Dr. Benjamin N. Greenberg, commented after the session that with the expected approvals of several oral agents over the next few years, “I'm getting concerned that there's going to be a little bit of a free-for-all coming.” But he added, “It's good to have options. We're all thrilled.”

The only head-to-head comparison of an oral therapy against another active treatment for multiple sclerosis so far is a study of fingolimod vs. interferon, he noted. Direct comparisons of the various oral agents will be needed to help clinicians develop treatment strategies, said Dr. Greenberg, a neurologist at the University of Texas Southwestern Medical Center, Dallas.

Gilenya may have some superior efficacy, compared with once-weekly interferon dosing, Dr. Kita said, but its potential adverse cardiovascular effects and “downstream consequences in terms of effects on different organ systems makes another oral daily alternative with less toxicity that much more appealing.”

Dr. Aaron Miller of Mount Sinai School of Medicine, New York, and Dr. Jerry S. Wolinsky of the University of Texas, Houston, presented results of the Teriflunomide Multiple Sclerosis Oral (TEMSO) trial during the session. The multinational, double-blind study randomized 1,088 patients with relapsing-remitting multiple sclerosis to a single daily dose of 7 mg or 14 mg of teriflunomide or placebo for 2 years.

Both doses reduced the annualized relapse rate by approximately 31%, compared with placebo. The annualized relapse rate was 0.37 in each of the treatment groups and 0.54 in the placebo group. The risk of disability progression also was significantly reduced by 30% in the 14-mg group but was not significantly different in the 7-mg group, compared with placebo.

Both doses showed significant improvements, compared with placebo, in brain disease activity on various MRI tests, although some MRI measures of disease activity were significantly better only in the high-dose group, compared with placebo.

Results of the 2-year, randomized, double-blind study of laquinimod that was presented earlier at the meeting showed an annual relapse rate of 0.304 on laquinimod, a 23% reduction compared with a rate of 0.395 on placebo. The laquinimod group also showed 33% less brain atrophy and significant improvements in brain disease activity on various MRI measures.

Both teriflunomide and laquinimod seemed relatively well tolerated, but among 11 women who became pregnant in the TEMSO study, 3 of 4 spontaneous abortions occurred in the teriflunomide groups. Six of the other pregnant women underwent induced abortions, and one woman successfully delivered a healthy baby.

“I thought that the teriflunomide study was interesting. It was impressive to see that a fairly low dose like that, which seems to be very well tolerated, could have effects on both the MRI and on the clinical end points,” Dr. Kita said. “My concern for it is making sure that we understand what the impact is on the female population, on the childbearing years.”

Dr. Kita said she has no relevant conflicts of interest. Dr. Greenberg disclosed financial relationships with DioGenix, Biogen Idec (which is developing BG-12), EMD Serono (which is developing cladribine), Teva Neurosciences (which is developing laquinimod), and the Greater Good Foundation.

Sanofi-Aventis, which is developing teriflunomide, funded TEMSO. Dr. Miller, Dr. Wolinsky, and many of their associates in the study disclosed relationships with Sanofi-Aventis and with numerous other companies that make therapies for multiple sclerosis. Three coinvestigators were employees of Sanofi-Aventis.

The challenge of the oral drugs will come from a lack of guidance on which drug or drugs to prioritize in treatment.

Source DR. KITA

Both teriflunomide doses reduced the annualized relapse rate by approximately 31%, compared with placebo.

Source DR. MILLER

HONOLULU – Oral therapies for relapsing-remitting multiple sclerosis that are in development have neurologists feeling both excited and a bit apprehensive.

“There are a whole slew of orals coming,” Dr. Mariko Kita said in an interview at the meetingo “It's really exciting, but I think it will be challenging for the clinician” because there will be inadequate guidance on which drug or drugs to prioritize in treatment and how best to combine various therapies.

“I think it's going to be very intimidating, actually,” said Dr. Kita, director of the multiple sclerosis center at Virginia Mason Medical Center, Seattle.

She comoderated a session on multiple sclerosis trials that included a report on a pooled analysis of safety data on the only approved oral therapy for multiple sclerosis, fingolimod (Gilenya). (See story on p. 10.) The session also included positive phase III clinical trial results for the experimental oral therapy teriflunomide. Earlier in the meeting, separate investigators reported positive phase III clinical trial results for the experimental oral therapy laquinimod.

Another oral agent under study, BG-12 (dimethyl fumarate), received Fast Track designation from the Food and Drug Administration and is in phase III clinical trials. Cladribine (Leustatin), which is currently marketed as chemotherapy for certain leukemias and lymphomas, initially was rejected by the FDA when it was submitted for approval as an oral therapy for multiple sclerosis. Following resubmission by the manufacturer, the FDA in early 2011 sent a letter to the company acknowledging sufficient data on the drug's efficacy in multiple sclerosis but requiring more data on safety and risk-benefit considerations before it could be approved.

Dr. Kita's comoderator, Dr. Benjamin N. Greenberg, commented after the session that with the expected approvals of several oral agents over the next few years, “I'm getting concerned that there's going to be a little bit of a free-for-all coming.” But he added, “It's good to have options. We're all thrilled.”

The only head-to-head comparison of an oral therapy against another active treatment for multiple sclerosis so far is a study of fingolimod vs. interferon, he noted. Direct comparisons of the various oral agents will be needed to help clinicians develop treatment strategies, said Dr. Greenberg, a neurologist at the University of Texas Southwestern Medical Center, Dallas.

Gilenya may have some superior efficacy, compared with once-weekly interferon dosing, Dr. Kita said, but its potential adverse cardiovascular effects and “downstream consequences in terms of effects on different organ systems makes another oral daily alternative with less toxicity that much more appealing.”

Dr. Aaron Miller of Mount Sinai School of Medicine, New York, and Dr. Jerry S. Wolinsky of the University of Texas, Houston, presented results of the Teriflunomide Multiple Sclerosis Oral (TEMSO) trial during the session. The multinational, double-blind study randomized 1,088 patients with relapsing-remitting multiple sclerosis to a single daily dose of 7 mg or 14 mg of teriflunomide or placebo for 2 years.

Both doses reduced the annualized relapse rate by approximately 31%, compared with placebo. The annualized relapse rate was 0.37 in each of the treatment groups and 0.54 in the placebo group. The risk of disability progression also was significantly reduced by 30% in the 14-mg group but was not significantly different in the 7-mg group, compared with placebo.

Both doses showed significant improvements, compared with placebo, in brain disease activity on various MRI tests, although some MRI measures of disease activity were significantly better only in the high-dose group, compared with placebo.

Results of the 2-year, randomized, double-blind study of laquinimod that was presented earlier at the meeting showed an annual relapse rate of 0.304 on laquinimod, a 23% reduction compared with a rate of 0.395 on placebo. The laquinimod group also showed 33% less brain atrophy and significant improvements in brain disease activity on various MRI measures.

Both teriflunomide and laquinimod seemed relatively well tolerated, but among 11 women who became pregnant in the TEMSO study, 3 of 4 spontaneous abortions occurred in the teriflunomide groups. Six of the other pregnant women underwent induced abortions, and one woman successfully delivered a healthy baby.

“I thought that the teriflunomide study was interesting. It was impressive to see that a fairly low dose like that, which seems to be very well tolerated, could have effects on both the MRI and on the clinical end points,” Dr. Kita said. “My concern for it is making sure that we understand what the impact is on the female population, on the childbearing years.”

Dr. Kita said she has no relevant conflicts of interest. Dr. Greenberg disclosed financial relationships with DioGenix, Biogen Idec (which is developing BG-12), EMD Serono (which is developing cladribine), Teva Neurosciences (which is developing laquinimod), and the Greater Good Foundation.

Sanofi-Aventis, which is developing teriflunomide, funded TEMSO. Dr. Miller, Dr. Wolinsky, and many of their associates in the study disclosed relationships with Sanofi-Aventis and with numerous other companies that make therapies for multiple sclerosis. Three coinvestigators were employees of Sanofi-Aventis.

The challenge of the oral drugs will come from a lack of guidance on which drug or drugs to prioritize in treatment.

Source DR. KITA

Both teriflunomide doses reduced the annualized relapse rate by approximately 31%, compared with placebo.

Source DR. MILLER

HONOLULU – Oral therapies for relapsing-remitting multiple sclerosis that are in development have neurologists feeling both excited and a bit apprehensive.

“There are a whole slew of orals coming,” Dr. Mariko Kita said in an interview at the meetingo “It's really exciting, but I think it will be challenging for the clinician” because there will be inadequate guidance on which drug or drugs to prioritize in treatment and how best to combine various therapies.

“I think it's going to be very intimidating, actually,” said Dr. Kita, director of the multiple sclerosis center at Virginia Mason Medical Center, Seattle.

She comoderated a session on multiple sclerosis trials that included a report on a pooled analysis of safety data on the only approved oral therapy for multiple sclerosis, fingolimod (Gilenya). (See story on p. 10.) The session also included positive phase III clinical trial results for the experimental oral therapy teriflunomide. Earlier in the meeting, separate investigators reported positive phase III clinical trial results for the experimental oral therapy laquinimod.

Another oral agent under study, BG-12 (dimethyl fumarate), received Fast Track designation from the Food and Drug Administration and is in phase III clinical trials. Cladribine (Leustatin), which is currently marketed as chemotherapy for certain leukemias and lymphomas, initially was rejected by the FDA when it was submitted for approval as an oral therapy for multiple sclerosis. Following resubmission by the manufacturer, the FDA in early 2011 sent a letter to the company acknowledging sufficient data on the drug's efficacy in multiple sclerosis but requiring more data on safety and risk-benefit considerations before it could be approved.

Dr. Kita's comoderator, Dr. Benjamin N. Greenberg, commented after the session that with the expected approvals of several oral agents over the next few years, “I'm getting concerned that there's going to be a little bit of a free-for-all coming.” But he added, “It's good to have options. We're all thrilled.”

The only head-to-head comparison of an oral therapy against another active treatment for multiple sclerosis so far is a study of fingolimod vs. interferon, he noted. Direct comparisons of the various oral agents will be needed to help clinicians develop treatment strategies, said Dr. Greenberg, a neurologist at the University of Texas Southwestern Medical Center, Dallas.

Gilenya may have some superior efficacy, compared with once-weekly interferon dosing, Dr. Kita said, but its potential adverse cardiovascular effects and “downstream consequences in terms of effects on different organ systems makes another oral daily alternative with less toxicity that much more appealing.”

Dr. Aaron Miller of Mount Sinai School of Medicine, New York, and Dr. Jerry S. Wolinsky of the University of Texas, Houston, presented results of the Teriflunomide Multiple Sclerosis Oral (TEMSO) trial during the session. The multinational, double-blind study randomized 1,088 patients with relapsing-remitting multiple sclerosis to a single daily dose of 7 mg or 14 mg of teriflunomide or placebo for 2 years.

Both doses reduced the annualized relapse rate by approximately 31%, compared with placebo. The annualized relapse rate was 0.37 in each of the treatment groups and 0.54 in the placebo group. The risk of disability progression also was significantly reduced by 30% in the 14-mg group but was not significantly different in the 7-mg group, compared with placebo.

Both doses showed significant improvements, compared with placebo, in brain disease activity on various MRI tests, although some MRI measures of disease activity were significantly better only in the high-dose group, compared with placebo.

Results of the 2-year, randomized, double-blind study of laquinimod that was presented earlier at the meeting showed an annual relapse rate of 0.304 on laquinimod, a 23% reduction compared with a rate of 0.395 on placebo. The laquinimod group also showed 33% less brain atrophy and significant improvements in brain disease activity on various MRI measures.

Both teriflunomide and laquinimod seemed relatively well tolerated, but among 11 women who became pregnant in the TEMSO study, 3 of 4 spontaneous abortions occurred in the teriflunomide groups. Six of the other pregnant women underwent induced abortions, and one woman successfully delivered a healthy baby.

“I thought that the teriflunomide study was interesting. It was impressive to see that a fairly low dose like that, which seems to be very well tolerated, could have effects on both the MRI and on the clinical end points,” Dr. Kita said. “My concern for it is making sure that we understand what the impact is on the female population, on the childbearing years.”

Dr. Kita said she has no relevant conflicts of interest. Dr. Greenberg disclosed financial relationships with DioGenix, Biogen Idec (which is developing BG-12), EMD Serono (which is developing cladribine), Teva Neurosciences (which is developing laquinimod), and the Greater Good Foundation.

Sanofi-Aventis, which is developing teriflunomide, funded TEMSO. Dr. Miller, Dr. Wolinsky, and many of their associates in the study disclosed relationships with Sanofi-Aventis and with numerous other companies that make therapies for multiple sclerosis. Three coinvestigators were employees of Sanofi-Aventis.

The challenge of the oral drugs will come from a lack of guidance on which drug or drugs to prioritize in treatment.

Source DR. KITA

Both teriflunomide doses reduced the annualized relapse rate by approximately 31%, compared with placebo.

Source DR. MILLER

Major Finding: Immune responses to tetanus toxoid immunization occurred by 28 days in 15 of 16 patients taking natalizumab and in all 24 control patients.

Data Source: Open-label, multicenter, randomized study of 60 patients with relapsing-remitting multiple sclerosis.

Disclosures: Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded the study. Dr. Pardo disclosed financial relationships with Biogen Idec, Acorda, Bayer, EMD Serono, Novartis, Pfizer, and Teva Neuroscience. A coinvestigator disclosed relationships with these and other companies, and two other coinvestigators were employees of Biogen Idec.

HONOLULU – Patients taking natalizumab showed similar or only slightly delayed humoral immune responses following vaccinations, compared with patients not taking the drug for relapsing-remitting multiple sclerosis in a multicenter, randomized, open-label study.

Natalizumab (Tysabri) acts as an immunomodulator, which raised questions about its potential effects on patients' responses to neoantigens and recall antigens. Previous studies have shown that some other biologic immunomodulatory drugs reduce antibody responses in patients, said Dr. Gabriel Pardo, director of the Oklahoma Medical Research Foundation's Multiple Sclerosis Center of Excellence, Oklahoma City.

Dr. Pardo and his associates studied 30 patients who had been taking natalizumab (Tysabri) for 6 months to treat their multiple sclerosis and 30 others with the disease who had never taken the drug. All 60 patients received a single tetanus toxoid vaccination in order to assess memory antibody responses to a recall antigen. At least 2 weeks later, they also received three keyhole limpet hemocyanin (KLH) vaccinations in order to assess de novo antibody responses.

Overall, 27 patients in the control group and 24 in the natalizumab group completed the study. None stopped the drug or dropped out of the study because of drug-related side effects.

A similar proportion of both groups responded to the tetanus immunization within 28 days − 15 of 16 patients in the natalizumab group (94%) and all of 24 control patients. The difference between groups was not statistically significant, Dr. Pardo and his associates reported at the meeting.

The one patient in the natalizumab group who did not respond within 28 days had a clinical response at 56 days after immunization.

Responses were defined as at least a twofold increase in specific serum immunoglobulin G (IgG) by 28 days after immunization, compared with baseline levels.

Median antitetanus toxoid antibody levels measured before and after immunization were similar between groups.

Antibody responses to the KLH vaccines also were similar between groups at 14, 28, and 56 days after immunizations. Anti-KLH antibody levels were similar between groups at all time points.

In the natalizumab group, the numbers of various lymphocytes increased over time, including CD3-positive, CD4-positive, and CD8-positive lymphocytes and B cells and natural killer (NK) cells. The investigators did not analyze humoral responses to live vaccines.

Adverse events were seen in 26 of 30 patients on natalizumab, which were most commonly disease relapse (5 patients) and influenza, paresthesia, or injection site reaction, each of which occurred in 4 patients.

Antitetanus toxoid antibody levels measured before and after immunization were similar between groups.

Source DR. PARDO

Major Finding: Immune responses to tetanus toxoid immunization occurred by 28 days in 15 of 16 patients taking natalizumab and in all 24 control patients.

Data Source: Open-label, multicenter, randomized study of 60 patients with relapsing-remitting multiple sclerosis.

Disclosures: Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded the study. Dr. Pardo disclosed financial relationships with Biogen Idec, Acorda, Bayer, EMD Serono, Novartis, Pfizer, and Teva Neuroscience. A coinvestigator disclosed relationships with these and other companies, and two other coinvestigators were employees of Biogen Idec.

HONOLULU – Patients taking natalizumab showed similar or only slightly delayed humoral immune responses following vaccinations, compared with patients not taking the drug for relapsing-remitting multiple sclerosis in a multicenter, randomized, open-label study.

Natalizumab (Tysabri) acts as an immunomodulator, which raised questions about its potential effects on patients' responses to neoantigens and recall antigens. Previous studies have shown that some other biologic immunomodulatory drugs reduce antibody responses in patients, said Dr. Gabriel Pardo, director of the Oklahoma Medical Research Foundation's Multiple Sclerosis Center of Excellence, Oklahoma City.

Dr. Pardo and his associates studied 30 patients who had been taking natalizumab (Tysabri) for 6 months to treat their multiple sclerosis and 30 others with the disease who had never taken the drug. All 60 patients received a single tetanus toxoid vaccination in order to assess memory antibody responses to a recall antigen. At least 2 weeks later, they also received three keyhole limpet hemocyanin (KLH) vaccinations in order to assess de novo antibody responses.

Overall, 27 patients in the control group and 24 in the natalizumab group completed the study. None stopped the drug or dropped out of the study because of drug-related side effects.

A similar proportion of both groups responded to the tetanus immunization within 28 days − 15 of 16 patients in the natalizumab group (94%) and all of 24 control patients. The difference between groups was not statistically significant, Dr. Pardo and his associates reported at the meeting.

The one patient in the natalizumab group who did not respond within 28 days had a clinical response at 56 days after immunization.

Responses were defined as at least a twofold increase in specific serum immunoglobulin G (IgG) by 28 days after immunization, compared with baseline levels.

Median antitetanus toxoid antibody levels measured before and after immunization were similar between groups.

Antibody responses to the KLH vaccines also were similar between groups at 14, 28, and 56 days after immunizations. Anti-KLH antibody levels were similar between groups at all time points.

In the natalizumab group, the numbers of various lymphocytes increased over time, including CD3-positive, CD4-positive, and CD8-positive lymphocytes and B cells and natural killer (NK) cells. The investigators did not analyze humoral responses to live vaccines.

Adverse events were seen in 26 of 30 patients on natalizumab, which were most commonly disease relapse (5 patients) and influenza, paresthesia, or injection site reaction, each of which occurred in 4 patients.

Antitetanus toxoid antibody levels measured before and after immunization were similar between groups.

Source DR. PARDO

Major Finding: Immune responses to tetanus toxoid immunization occurred by 28 days in 15 of 16 patients taking natalizumab and in all 24 control patients.

Data Source: Open-label, multicenter, randomized study of 60 patients with relapsing-remitting multiple sclerosis.

Disclosures: Biogen Idec and Elan Pharmaceuticals, which comarket Tysabri, funded the study. Dr. Pardo disclosed financial relationships with Biogen Idec, Acorda, Bayer, EMD Serono, Novartis, Pfizer, and Teva Neuroscience. A coinvestigator disclosed relationships with these and other companies, and two other coinvestigators were employees of Biogen Idec.

HONOLULU – Patients taking natalizumab showed similar or only slightly delayed humoral immune responses following vaccinations, compared with patients not taking the drug for relapsing-remitting multiple sclerosis in a multicenter, randomized, open-label study.

Natalizumab (Tysabri) acts as an immunomodulator, which raised questions about its potential effects on patients' responses to neoantigens and recall antigens. Previous studies have shown that some other biologic immunomodulatory drugs reduce antibody responses in patients, said Dr. Gabriel Pardo, director of the Oklahoma Medical Research Foundation's Multiple Sclerosis Center of Excellence, Oklahoma City.

Dr. Pardo and his associates studied 30 patients who had been taking natalizumab (Tysabri) for 6 months to treat their multiple sclerosis and 30 others with the disease who had never taken the drug. All 60 patients received a single tetanus toxoid vaccination in order to assess memory antibody responses to a recall antigen. At least 2 weeks later, they also received three keyhole limpet hemocyanin (KLH) vaccinations in order to assess de novo antibody responses.

Overall, 27 patients in the control group and 24 in the natalizumab group completed the study. None stopped the drug or dropped out of the study because of drug-related side effects.

A similar proportion of both groups responded to the tetanus immunization within 28 days − 15 of 16 patients in the natalizumab group (94%) and all of 24 control patients. The difference between groups was not statistically significant, Dr. Pardo and his associates reported at the meeting.

The one patient in the natalizumab group who did not respond within 28 days had a clinical response at 56 days after immunization.

Responses were defined as at least a twofold increase in specific serum immunoglobulin G (IgG) by 28 days after immunization, compared with baseline levels.

Median antitetanus toxoid antibody levels measured before and after immunization were similar between groups.

Antibody responses to the KLH vaccines also were similar between groups at 14, 28, and 56 days after immunizations. Anti-KLH antibody levels were similar between groups at all time points.

In the natalizumab group, the numbers of various lymphocytes increased over time, including CD3-positive, CD4-positive, and CD8-positive lymphocytes and B cells and natural killer (NK) cells. The investigators did not analyze humoral responses to live vaccines.

Adverse events were seen in 26 of 30 patients on natalizumab, which were most commonly disease relapse (5 patients) and influenza, paresthesia, or injection site reaction, each of which occurred in 4 patients.

Antitetanus toxoid antibody levels measured before and after immunization were similar between groups.

Source DR. PARDO

Major Finding: Transient reductions in heart rate on fingolimod hit a nadir at 4–5 hours after starting therapy and then increased to baseline over time, whereas reductions in atrioventricular conduction that began within the first 6 hours after starting therapy became attenuated and reached baseline levels by 1 month; increases in blood pressure of 1–3 mm Hg starting 2–6 months into treatment were sustained.

Data Source: Analysis of pooled data on 2,552 patients in two phase III clinical trials of fingolimod for relapsing-remitting multiple sclerosis.

Disclosures: The analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis and other pharmaceutical companies. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1–2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist's office.

Heart rates hit a nadir approximately 4–5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the meetingo By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, inteferon therapy causedsome tachycardia.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35–39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40–44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45–54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55–64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in other groups. All were described as mildly or moderately severe.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2–6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1–2 mm Hg on 0.5 mg/day fingolimod and 1–3 mm Hg on 1.25 mg/day fingolimod, compared with placebo.

Rates of hypertension adverse events were higher in the fingolimod groups − 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Major Finding: Transient reductions in heart rate on fingolimod hit a nadir at 4–5 hours after starting therapy and then increased to baseline over time, whereas reductions in atrioventricular conduction that began within the first 6 hours after starting therapy became attenuated and reached baseline levels by 1 month; increases in blood pressure of 1–3 mm Hg starting 2–6 months into treatment were sustained.

Data Source: Analysis of pooled data on 2,552 patients in two phase III clinical trials of fingolimod for relapsing-remitting multiple sclerosis.

Disclosures: The analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis and other pharmaceutical companies. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1–2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist's office.

Heart rates hit a nadir approximately 4–5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the meetingo By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, inteferon therapy causedsome tachycardia.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35–39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40–44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45–54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55–64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in other groups. All were described as mildly or moderately severe.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2–6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1–2 mm Hg on 0.5 mg/day fingolimod and 1–3 mm Hg on 1.25 mg/day fingolimod, compared with placebo.

Rates of hypertension adverse events were higher in the fingolimod groups − 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

Major Finding: Transient reductions in heart rate on fingolimod hit a nadir at 4–5 hours after starting therapy and then increased to baseline over time, whereas reductions in atrioventricular conduction that began within the first 6 hours after starting therapy became attenuated and reached baseline levels by 1 month; increases in blood pressure of 1–3 mm Hg starting 2–6 months into treatment were sustained.

Data Source: Analysis of pooled data on 2,552 patients in two phase III clinical trials of fingolimod for relapsing-remitting multiple sclerosis.

Disclosures: The analysis was funded by Novartis, which markets fingolimod. Dr. DiMarco disclosed financial relationships with Novartis and other pharmaceutical companies. His associates in the study have been employees of Novartis, have held stock in the company, or disclosed other financial relationships with Novartis and other pharmaceutical companies.

HONOLULU – The first approved oral medication for multiple sclerosis causes transient reductions in heart rate and atrioventricular conduction and a sustained increase in blood pressure, according to investigators who analyzed pooled data from two phase III trials.

The cohorts from the two phase III clinical trials of fingolimod (Gilenya) for relapsing-remitting muscular sclerosis involved 854 patients treated with the currently approved dosage of fingolimod (0.5 mg/day), 849 patients on a higher dosage (1.25 mg/day), 418 patients on placebo, and 431 patients treated with weekly intramuscular injections of 30 mcg interferon beta-1a (Avonex) for 1–2 years.

The investigators measured vital signs hourly for 6 hours after starting treatment and at quarterly follow-up visits. Patients underwent an ECG before the first dose, 6 hours after treatment initiation, and if they developed symptoms during those 6 hours, as well as at selected follow-up visits. The studies did not use continuous ECG monitoring because they were designed to mimic treatment initiation in a neurologist's office.

Heart rates hit a nadir approximately 4–5 hours after starting fingolimod, and then began to increase, Dr. John DiMarco reported at the meetingo By 2 weeks after starting therapy, heart rates in the fingolimod groups were almost back to baseline, and thereafter were similar to baseline heart rates in the placebo group. As expected, inteferon therapy causedsome tachycardia.

In the first 6 hours of treatment, the lowest measured heart rate was below 35 beats per minute (bpm) in one patient on fingolimod 1.25 mg/day and one patient on interferon. Heart rates fell to as low as 35–39 bpm in six patients on fingolimod 1.25 mg/day, reported Dr. DiMarco, a cardiologist and professor of medicine at the University of Virginia, Charlottesville.

A heart rate nadir of 40–44 bpm was seen in approximately 1% of the low-dose fingolimod group, 3% of the high-dose fingolimod group, 0.2% of the placebo group, and no patients on interferon. A nadir of 45–54 bpm was measured in 18% on low-dose fingolimod, 29% on high-dose fingolimod, 6% on placebo, and 3% on interferon.

The lowest heart rate was 55–64 bpm in 49% on low-dose fingolimod, 50% on high-dose fingolimod, 37% on placebo, and 33% on interferon. Heart rates never fell below 65 bpm in 32% on low-dose fingolimod, 18% on high-dose fingolimod, 56% on placebo, and 64% on interferon.

Patients could be discharged at the 6-hour follow-up if any slowing in heart rate had started to return toward baseline, the heart rate was at least 55 bpm or greater than 80% of the baseline rate, and the patient had no symptoms related to bradycardia and no new, clinically relevant abnormality on ECG.

Observation beyond the 6-hour period was required in 12% on low-dose fingolimod, 18% on high-dose fingolimod, 3% on placebo, and 1% on interferon. Clinicians chose to hospitalize 2% of patients on fingolimod 0.5 mg/day, 3% of patients on 1.25 mg/day, 0.5% of patients on interferon, and none on placebo.

Symptoms of bradycardia were seen in 0.5% of patients on 0.5 mg/day fingolimod, 1% of patients on 1.25 mg/day, and no patients in other groups. All were described as mildly or moderately severe.

Conduction abnormalities also were more common within 6 hours of taking low-dose fingolimod (7%) or high-dose fingolimod (13%), compared with placebo or interferon (4% each). First-degree atrioventricular (AV) block was seen in 5% on low-dose fingolimod, 10% on high-dose fingolimod, 2% on placebo, and 3% on interferon. A Wenckebach second-degree AV block was seen in 0.2% on low-dose fingolimod, 0.7% on high-dose fingolimod, and no patients in the other groups. Two patients (0.2%) in the high-dose fingolimod group developed 2:1 second-degree AV block.

One patient in the low-dose fingolimod group and three in the high-dose fingolimod group were treated for heart rate or conduction abnormalities, although two of these patients were asymptomatic. Fingolimod was discontinued after the first dose in 1% of the high-dose group. In the others, the AV conduction changes attenuated with continued therapy and returned to baseline levels by 1 month.

The rise in blood pressure on fingolimod was small, but sustained and statistically significant, starting within 2–6 months of treatment initiation. Systolic and diastolic blood pressure increases averaged 1–2 mm Hg on 0.5 mg/day fingolimod and 1–3 mm Hg on 1.25 mg/day fingolimod, compared with placebo.

Rates of hypertension adverse events were higher in the fingolimod groups − 4% on the lower dose and 5% on the higher dose – compared with the placebo group (3%) or the interferon group (2%). The proportions of patients who needed antihypertensive therapy, however, were similar between groups: 5% on low-dose fingolimod, 6% on high-dose fingolimod, 6% on placebo, and 4% on interferon.

Patients who were treated responded to standard antihypertensive therapy.

Data for the analysis came from the Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis (FREEDOMS) trial and from the Trial Assessing Injectable Interferon vs. FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS). Both were international, multicenter, randomized double-blind trials.

An international panel has revised the McDonald criteria for the diagnosis of multiple sclerosis to simplify the use of imaging in determining the dissemination of central nervous system lesions both in space and time, while preserving sensitivity and specificity.

The new revisions also address the applicability of the criteria in non-Western Caucasian populations – specifically Asian and Latin American populations – and children and adolescents.

The changes update the 2005 version of the criteria based on new evidence and consensus, which “pointed to the need for their simplification to improve their comprehension and utility and for evaluating their appropriateness in populations that differ from the largely Western Caucasian adult population from which the criteria were derived,” wrote lead author Dr. Chris H. Polman and his coauthors (Ann. Neurol. 2011;69:292-302).

In an accompanying editorial, Dr. Richard A. Rudick agreed (Ann. Neurol. 2011;69:234-6). “The McDonald criteria were not just for clinical trials, but for neurologists in practice. However, some neurologists found the McDonald criteria complex and difficult to use in the clinic, and even experienced MS specialists were uncertain about some aspects of the criteria.” Dr. Rudick is the director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

The 2010 revisions to the McDonald criteria are intended to allow a more rapid diagnosis of MS in some instances, with equivalent or improved specificity or sensitivity, and will clarify and simplify the diagnostic process with fewer required MRI examinations, according to Dr. Polman of the neurology department at the Free University in Amsterdam, and his coauthors.

The International Panel on Diagnosis of MS reviewed published research related to the diagnosis of MS and to the original and revised McDonald criteria, gathered from literature searches of English-language publications.

The panel stressed that the updated criteria should be applied only to patients who present with a typical clinically isolated syndrome (CIS) suggestive of MS or symptoms consistent with a central nervous system (CNS) inflammatory demyelinating disease, because the development and validation of the criteria have been limited to patients with such presentations. It also remains imperative that alternative diagnoses be considered and excluded.

Neuromyelitis Optica and Spectrum Disorders

The panel focused on the differential diagnosis for MS of neuromyelitis optica (NMO) and NMO spectrum disorders, because “there is increasing evidence of relapsing CNS demyelinating disease characterized by involvement of optic nerves (unilateral or bilateral optic neuritis), often severe myelopathy with MRI evidence of longitudinally extensive spinal cord lesions, often normal brain MRI (or with abnormalities atypical for MS), and serum aquaporin-4 (AQP4) autoantibodies.”

The panel agreed that this phenotype should be separated out because the clinical course, prognosis, and underlying pathophysiology are different from those of typical MS. The response of patients with NMO and its spectrum disorders to some available MS disease-modifying therapies is often poor.

The panel recommended that this disorder should be carefully considered in the differential diagnosis of all patients presenting with clinical and MRI features that are strongly suggestive of NMO or NMO spectrum disorder, especially if:

▸ Myelopathy is associated with MRI-detected spinal cord lesions longer than three spinal segments and primarily involving the central part of the spinal cord on axial sections;

▸ Optic neuritis is bilateral and severe or associated with a swollen optic nerve or chiasm lesion or an altitudinal scotoma; and

▸ Intractable hiccough, nausea, or vomiting is present for more than 2 days with evidence of a periaqueductal medullary lesion on MRI.

AQP4 serum testing should be used to help make a differential diagnosis between NMO and MS.

Dissemination in Space and Time

While the panel agreed that the underlying concepts of the original (2001) and revised (2005) criteria are still valid, they recommended key changes related to the use and interpretation of imaging criteria for dissemination in space (DIS) and dissemination in time (DIT) as articulated by the recently published work from the Magnetic Imaging in MS (MAGNIMS) research group.

The European MAGNIMS multicenter collaborative research network compared the Barkhof/Tintoré criteria for DIS (Brain 1997;120:2059-69; Am. J. Neuroradiol. 2000;21:702-6) – used in previous McDonald criteria – with simplified criteria developed by Swanton and colleagues (Lancet Neurol. 2007;6: 677-86; J. Neurol. Neurosurg. Psychiatry 2006;77:830-3).

Based on the MAGNIMS analysis, the panel said that DIS can be demonstrated with at least one T2 lesion in at least two of four locations considered characteristic for MS (juxtacortical, periventricular, infratentorial, and spinal cord), excluding lesions within the symptomatic region in patients with brainstem or spinal cord syndromes.

These new criteria for DIS can simplify the diagnostic process for MS, while preserving specificity and improving sensitivity.

The presence of both gadolinium-enhancing and nonenhancing lesions on the baseline MRI can substitute for a follow-up scan to confirm DIT, as long as it can be reliably determined that the gadolinium-enhancing lesion is not due to non-MS pathology.

Based on these changes, a diagnosis of MS can be made in some CIS patients on the basis of a single MRI. The panel stated that this change simplifies the diagnostic process without reducing accuracy.

Cerebrospinal Fluid

The panel still agreed that positive cerebrospinal fluid (CSF) findings – elevated immunoglobulin G (IgG) index or two or more oligoclonal bands – can be important to support the inflammatory demyelinating nature of the underlying condition, to evaluate alternative diagnoses, and to predict clinically definite MS. However, when applying the simplified MAGNIMS imaging criteria for DIS and DIT, the panel believes that changing the MRI requirements in CSF-positive patients is not appropriate.

Primary Progressive MS

The panel recommended replacing previous brain imaging criteria for primary progressive MS (PPMS) with the new MAGNIMS criteria for DIS. In addition to 1 year of disease progression, the new criteria for PPMS require two of the following: at least one T2 lesion in at least one area characteristic for MS (periventricular, juxtacortical, or infratentorial); at least two T2 lesions in the cord; or positive CSF (isoelectric focusing evidence of oligoclonal bands with or without an elevated IgG index).

Dr. Polman, Dr. Rudick, and several other panelists reported significant financial relationships with several pharmaceutical companies.

An international panel has revised the McDonald criteria for the diagnosis of multiple sclerosis to simplify the use of imaging in determining the dissemination of central nervous system lesions both in space and time, while preserving sensitivity and specificity.

The new revisions also address the applicability of the criteria in non-Western Caucasian populations – specifically Asian and Latin American populations – and children and adolescents.

The changes update the 2005 version of the criteria based on new evidence and consensus, which “pointed to the need for their simplification to improve their comprehension and utility and for evaluating their appropriateness in populations that differ from the largely Western Caucasian adult population from which the criteria were derived,” wrote lead author Dr. Chris H. Polman and his coauthors (Ann. Neurol. 2011;69:292-302).

In an accompanying editorial, Dr. Richard A. Rudick agreed (Ann. Neurol. 2011;69:234-6). “The McDonald criteria were not just for clinical trials, but for neurologists in practice. However, some neurologists found the McDonald criteria complex and difficult to use in the clinic, and even experienced MS specialists were uncertain about some aspects of the criteria.” Dr. Rudick is the director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

The 2010 revisions to the McDonald criteria are intended to allow a more rapid diagnosis of MS in some instances, with equivalent or improved specificity or sensitivity, and will clarify and simplify the diagnostic process with fewer required MRI examinations, according to Dr. Polman of the neurology department at the Free University in Amsterdam, and his coauthors.

The International Panel on Diagnosis of MS reviewed published research related to the diagnosis of MS and to the original and revised McDonald criteria, gathered from literature searches of English-language publications.

The panel stressed that the updated criteria should be applied only to patients who present with a typical clinically isolated syndrome (CIS) suggestive of MS or symptoms consistent with a central nervous system (CNS) inflammatory demyelinating disease, because the development and validation of the criteria have been limited to patients with such presentations. It also remains imperative that alternative diagnoses be considered and excluded.

Neuromyelitis Optica and Spectrum Disorders

The panel focused on the differential diagnosis for MS of neuromyelitis optica (NMO) and NMO spectrum disorders, because “there is increasing evidence of relapsing CNS demyelinating disease characterized by involvement of optic nerves (unilateral or bilateral optic neuritis), often severe myelopathy with MRI evidence of longitudinally extensive spinal cord lesions, often normal brain MRI (or with abnormalities atypical for MS), and serum aquaporin-4 (AQP4) autoantibodies.”

The panel agreed that this phenotype should be separated out because the clinical course, prognosis, and underlying pathophysiology are different from those of typical MS. The response of patients with NMO and its spectrum disorders to some available MS disease-modifying therapies is often poor.

The panel recommended that this disorder should be carefully considered in the differential diagnosis of all patients presenting with clinical and MRI features that are strongly suggestive of NMO or NMO spectrum disorder, especially if:

▸ Myelopathy is associated with MRI-detected spinal cord lesions longer than three spinal segments and primarily involving the central part of the spinal cord on axial sections;

▸ Optic neuritis is bilateral and severe or associated with a swollen optic nerve or chiasm lesion or an altitudinal scotoma; and

▸ Intractable hiccough, nausea, or vomiting is present for more than 2 days with evidence of a periaqueductal medullary lesion on MRI.

AQP4 serum testing should be used to help make a differential diagnosis between NMO and MS.

Dissemination in Space and Time

While the panel agreed that the underlying concepts of the original (2001) and revised (2005) criteria are still valid, they recommended key changes related to the use and interpretation of imaging criteria for dissemination in space (DIS) and dissemination in time (DIT) as articulated by the recently published work from the Magnetic Imaging in MS (MAGNIMS) research group.

The European MAGNIMS multicenter collaborative research network compared the Barkhof/Tintoré criteria for DIS (Brain 1997;120:2059-69; Am. J. Neuroradiol. 2000;21:702-6) – used in previous McDonald criteria – with simplified criteria developed by Swanton and colleagues (Lancet Neurol. 2007;6: 677-86; J. Neurol. Neurosurg. Psychiatry 2006;77:830-3).

Based on the MAGNIMS analysis, the panel said that DIS can be demonstrated with at least one T2 lesion in at least two of four locations considered characteristic for MS (juxtacortical, periventricular, infratentorial, and spinal cord), excluding lesions within the symptomatic region in patients with brainstem or spinal cord syndromes.

These new criteria for DIS can simplify the diagnostic process for MS, while preserving specificity and improving sensitivity.

The presence of both gadolinium-enhancing and nonenhancing lesions on the baseline MRI can substitute for a follow-up scan to confirm DIT, as long as it can be reliably determined that the gadolinium-enhancing lesion is not due to non-MS pathology.

Based on these changes, a diagnosis of MS can be made in some CIS patients on the basis of a single MRI. The panel stated that this change simplifies the diagnostic process without reducing accuracy.

Cerebrospinal Fluid

The panel still agreed that positive cerebrospinal fluid (CSF) findings – elevated immunoglobulin G (IgG) index or two or more oligoclonal bands – can be important to support the inflammatory demyelinating nature of the underlying condition, to evaluate alternative diagnoses, and to predict clinically definite MS. However, when applying the simplified MAGNIMS imaging criteria for DIS and DIT, the panel believes that changing the MRI requirements in CSF-positive patients is not appropriate.

Primary Progressive MS

The panel recommended replacing previous brain imaging criteria for primary progressive MS (PPMS) with the new MAGNIMS criteria for DIS. In addition to 1 year of disease progression, the new criteria for PPMS require two of the following: at least one T2 lesion in at least one area characteristic for MS (periventricular, juxtacortical, or infratentorial); at least two T2 lesions in the cord; or positive CSF (isoelectric focusing evidence of oligoclonal bands with or without an elevated IgG index).

Dr. Polman, Dr. Rudick, and several other panelists reported significant financial relationships with several pharmaceutical companies.

An international panel has revised the McDonald criteria for the diagnosis of multiple sclerosis to simplify the use of imaging in determining the dissemination of central nervous system lesions both in space and time, while preserving sensitivity and specificity.

The new revisions also address the applicability of the criteria in non-Western Caucasian populations – specifically Asian and Latin American populations – and children and adolescents.

The changes update the 2005 version of the criteria based on new evidence and consensus, which “pointed to the need for their simplification to improve their comprehension and utility and for evaluating their appropriateness in populations that differ from the largely Western Caucasian adult population from which the criteria were derived,” wrote lead author Dr. Chris H. Polman and his coauthors (Ann. Neurol. 2011;69:292-302).

In an accompanying editorial, Dr. Richard A. Rudick agreed (Ann. Neurol. 2011;69:234-6). “The McDonald criteria were not just for clinical trials, but for neurologists in practice. However, some neurologists found the McDonald criteria complex and difficult to use in the clinic, and even experienced MS specialists were uncertain about some aspects of the criteria.” Dr. Rudick is the director of the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.

The 2010 revisions to the McDonald criteria are intended to allow a more rapid diagnosis of MS in some instances, with equivalent or improved specificity or sensitivity, and will clarify and simplify the diagnostic process with fewer required MRI examinations, according to Dr. Polman of the neurology department at the Free University in Amsterdam, and his coauthors.

The International Panel on Diagnosis of MS reviewed published research related to the diagnosis of MS and to the original and revised McDonald criteria, gathered from literature searches of English-language publications.

The panel stressed that the updated criteria should be applied only to patients who present with a typical clinically isolated syndrome (CIS) suggestive of MS or symptoms consistent with a central nervous system (CNS) inflammatory demyelinating disease, because the development and validation of the criteria have been limited to patients with such presentations. It also remains imperative that alternative diagnoses be considered and excluded.

Neuromyelitis Optica and Spectrum Disorders

The panel focused on the differential diagnosis for MS of neuromyelitis optica (NMO) and NMO spectrum disorders, because “there is increasing evidence of relapsing CNS demyelinating disease characterized by involvement of optic nerves (unilateral or bilateral optic neuritis), often severe myelopathy with MRI evidence of longitudinally extensive spinal cord lesions, often normal brain MRI (or with abnormalities atypical for MS), and serum aquaporin-4 (AQP4) autoantibodies.”

The panel agreed that this phenotype should be separated out because the clinical course, prognosis, and underlying pathophysiology are different from those of typical MS. The response of patients with NMO and its spectrum disorders to some available MS disease-modifying therapies is often poor.

The panel recommended that this disorder should be carefully considered in the differential diagnosis of all patients presenting with clinical and MRI features that are strongly suggestive of NMO or NMO spectrum disorder, especially if:

▸ Myelopathy is associated with MRI-detected spinal cord lesions longer than three spinal segments and primarily involving the central part of the spinal cord on axial sections;

▸ Optic neuritis is bilateral and severe or associated with a swollen optic nerve or chiasm lesion or an altitudinal scotoma; and

▸ Intractable hiccough, nausea, or vomiting is present for more than 2 days with evidence of a periaqueductal medullary lesion on MRI.

AQP4 serum testing should be used to help make a differential diagnosis between NMO and MS.

Dissemination in Space and Time

While the panel agreed that the underlying concepts of the original (2001) and revised (2005) criteria are still valid, they recommended key changes related to the use and interpretation of imaging criteria for dissemination in space (DIS) and dissemination in time (DIT) as articulated by the recently published work from the Magnetic Imaging in MS (MAGNIMS) research group.

The European MAGNIMS multicenter collaborative research network compared the Barkhof/Tintoré criteria for DIS (Brain 1997;120:2059-69; Am. J. Neuroradiol. 2000;21:702-6) – used in previous McDonald criteria – with simplified criteria developed by Swanton and colleagues (Lancet Neurol. 2007;6: 677-86; J. Neurol. Neurosurg. Psychiatry 2006;77:830-3).

Based on the MAGNIMS analysis, the panel said that DIS can be demonstrated with at least one T2 lesion in at least two of four locations considered characteristic for MS (juxtacortical, periventricular, infratentorial, and spinal cord), excluding lesions within the symptomatic region in patients with brainstem or spinal cord syndromes.

These new criteria for DIS can simplify the diagnostic process for MS, while preserving specificity and improving sensitivity.

The presence of both gadolinium-enhancing and nonenhancing lesions on the baseline MRI can substitute for a follow-up scan to confirm DIT, as long as it can be reliably determined that the gadolinium-enhancing lesion is not due to non-MS pathology.

Based on these changes, a diagnosis of MS can be made in some CIS patients on the basis of a single MRI. The panel stated that this change simplifies the diagnostic process without reducing accuracy.

Cerebrospinal Fluid

The panel still agreed that positive cerebrospinal fluid (CSF) findings – elevated immunoglobulin G (IgG) index or two or more oligoclonal bands – can be important to support the inflammatory demyelinating nature of the underlying condition, to evaluate alternative diagnoses, and to predict clinically definite MS. However, when applying the simplified MAGNIMS imaging criteria for DIS and DIT, the panel believes that changing the MRI requirements in CSF-positive patients is not appropriate.

Primary Progressive MS

The panel recommended replacing previous brain imaging criteria for primary progressive MS (PPMS) with the new MAGNIMS criteria for DIS. In addition to 1 year of disease progression, the new criteria for PPMS require two of the following: at least one T2 lesion in at least one area characteristic for MS (periventricular, juxtacortical, or infratentorial); at least two T2 lesions in the cord; or positive CSF (isoelectric focusing evidence of oligoclonal bands with or without an elevated IgG index).

Dr. Polman, Dr. Rudick, and several other panelists reported significant financial relationships with several pharmaceutical companies.

HONOLULU – Two years of taking the investigational oral drug laquinimod reduced multiple sclerosis relapses and slowed progression toward disability and brain atrophy, compared with placebo, in a phase III study of 1,106 patients with relapsing-remitting multiple sclerosis.

The annualized relapse rate declined by 23% among patients who took laquinimod 0.6 mg daily in the randomized trial, which involved 139 centers in 24 countries, Dr. Giancarlo Comi and his associates reported at the meetingo The annualized relapse rates were 0.304 on laquinimod and 0.395 on placebo.

The laquinimod group also showed a 36% reduction in disability progression, which “is quite a big thing, more than what has been reported” in previous drug studies, said Dr. Comi, director of the department of neurology and the institute of experimental neurology at the Scientific Institute and University of Vita-Salute San Raffaele, Milan.

Most importantly, he said in an interview, the laquinimod group showed 33% less brain atrophy over the course of the study. “That's interesting because most drugs fail to have an effect on this,” he said.

These multiple benefits may be tied to laquinimod's novel mechanism of action, which addresses both the disease's acute inflammatory activity and the accumulation of irreversible tissue damage, he said.

The results suggest that laquinimod is a “very promising” treatment, Dr. Comi said. “In the end, what matters is how much damage there is to the patient and how much the drug was able to prevent that.”

Baseline characteristics of the two groups were similar, including demographics, clinical factors and MRI findings. At the start of the study, 46% of the laquinimod group and 40% of the placebo group had active disease. Patients in both groups had had MS for an average of 9 years.

Patients underwent clinical evaluations every 3 months and yearly MRI exams. By the end of the study, the mean number of gadolinium-enhanced lesions on MRI was 37% lower in the laquinimod group and the mean number of new T2 lesions was 30% lower, compared with placebo. The mean number of new T1 lesions, which are characterized by more severe tissue damage, was 27% lower with the drug, compared with placebo.

Laquinimod appeared to be well tolerated. Seventy-nine percent of patients who were randomized to laquinimod and 77% of patients who were randomized to placebo finished the double-blind study.

Elevations of liver enzymes were more common in the laquinimod group (7%) than in the placebo group (3%), but these were transient and reversible and did not lead to signs of liver problems, Dr. Comi said. Liver enzyme elevations greater than three times the upper limit of normal occurred in 2% of the placebo group and 5% of the laquinimod group.

The overall rates of adverse events were low (22% on laquinimod and 16% on placebo) and did not differ significantly between the drug and placebo groups. Two patients on placebo died from unrelated causes, with no deaths in the laquinimod group. The laquinimod group reported higher rates of abdominal pain (5%) and back pain (16%), compared with placebo (3% and 9%, respectively).

In 2010, the oral medication fingolimod (Gilenya) was approved as adjunctive therapy for relapsing-remitting MS. Concerns about increased risks for cardiac problems, immune suppression, and cancer with fingolimod were not a problem in the laquinimod study, Dr. Comi said.

One patient in the placebo group developed pericarditis. There was no evidence of decreased immune function on laquinimod. For example, 17% on placebo on 20% on laquinimod developed herpes infection. There were six cases of cancer in the placebo group and eight in the laquinimod group, for rates of 1.1% and 1.5%, respectively.

A parallel trial is underway to confirm the findings, and results from that trial are expected in the fall of 2011, he said.

Teva Pharmaceuticals, which is developing laquinimod, funded the study. Dr. Comi has received compensation from Teva, Novartis, Sanofi-Aventis, Merck Serono, and Bayer Schering Pharma. Some of his associates in the study reported relationships with Teva and other companies manufacturing drugs for MS.

A parallel trial is underway to confirm the findings, and results from the trial are expected in the fall of 2011.

Source DR. COMI

View on The News

Drug Will Easily Find a Niche

The results were very positive on disease and on relapse rate reduction. These were both very good signs. In addition, laquinimod was a relatively or maybe very safe medication for people to take.

In contrast, some of the newer agents are having difficulty going through the phase III testing for approval. For example, one of the other agents has been held up in the Food and Drug Administration review because of safety concerns.

Another one that was just approved has risks for immune suppression. Laquinimod does not appear to have a risk for immune suppression, yet it has efficacy in relapsing-remitting MS.

Many patients who will tolerate one drug will not tolerate another drug, so it will be very easy to find a niche for this particular drug.

Most patients don't want an injectable therapy. On the other hand, we have to recognize that even an oral medication can pose some risks. Laquinimod does not seem to have any of those risks, but it causes immune modulation, so it may fit in early MS where it may show its greater efficacy.

What we've learned in the last 10 years – and most important of all – is not which drug to use, but when to treat, and to treat early, because treating early seems to be where we can see the best and most effect.

Laquinimod has a different mechanism of action. It seems to involve the signaling pathways that are in the innate immune system. We're learning about that now. There is going to be much more to be learned about this drug after it's approved in terms of its mechanisms of action.

SCOTT S. ZAMVIL, M.D., is professor of neurology at the University of California, San Francisco. He was not associated with the laquinimod study. He has been a consultant for Teva Pharmaceuticals, Biogen Idec, and Serono. In addition, Dr. Zamvil has received grant support or served on data safety monitoring boards for multiple drug companies.

HONOLULU – Two years of taking the investigational oral drug laquinimod reduced multiple sclerosis relapses and slowed progression toward disability and brain atrophy, compared with placebo, in a phase III study of 1,106 patients with relapsing-remitting multiple sclerosis.

The annualized relapse rate declined by 23% among patients who took laquinimod 0.6 mg daily in the randomized trial, which involved 139 centers in 24 countries, Dr. Giancarlo Comi and his associates reported at the meetingo The annualized relapse rates were 0.304 on laquinimod and 0.395 on placebo.

The laquinimod group also showed a 36% reduction in disability progression, which “is quite a big thing, more than what has been reported” in previous drug studies, said Dr. Comi, director of the department of neurology and the institute of experimental neurology at the Scientific Institute and University of Vita-Salute San Raffaele, Milan.

Most importantly, he said in an interview, the laquinimod group showed 33% less brain atrophy over the course of the study. “That's interesting because most drugs fail to have an effect on this,” he said.

These multiple benefits may be tied to laquinimod's novel mechanism of action, which addresses both the disease's acute inflammatory activity and the accumulation of irreversible tissue damage, he said.

The results suggest that laquinimod is a “very promising” treatment, Dr. Comi said. “In the end, what matters is how much damage there is to the patient and how much the drug was able to prevent that.”

Baseline characteristics of the two groups were similar, including demographics, clinical factors and MRI findings. At the start of the study, 46% of the laquinimod group and 40% of the placebo group had active disease. Patients in both groups had had MS for an average of 9 years.

Patients underwent clinical evaluations every 3 months and yearly MRI exams. By the end of the study, the mean number of gadolinium-enhanced lesions on MRI was 37% lower in the laquinimod group and the mean number of new T2 lesions was 30% lower, compared with placebo. The mean number of new T1 lesions, which are characterized by more severe tissue damage, was 27% lower with the drug, compared with placebo.

Laquinimod appeared to be well tolerated. Seventy-nine percent of patients who were randomized to laquinimod and 77% of patients who were randomized to placebo finished the double-blind study.

Elevations of liver enzymes were more common in the laquinimod group (7%) than in the placebo group (3%), but these were transient and reversible and did not lead to signs of liver problems, Dr. Comi said. Liver enzyme elevations greater than three times the upper limit of normal occurred in 2% of the placebo group and 5% of the laquinimod group.

The overall rates of adverse events were low (22% on laquinimod and 16% on placebo) and did not differ significantly between the drug and placebo groups. Two patients on placebo died from unrelated causes, with no deaths in the laquinimod group. The laquinimod group reported higher rates of abdominal pain (5%) and back pain (16%), compared with placebo (3% and 9%, respectively).

In 2010, the oral medication fingolimod (Gilenya) was approved as adjunctive therapy for relapsing-remitting MS. Concerns about increased risks for cardiac problems, immune suppression, and cancer with fingolimod were not a problem in the laquinimod study, Dr. Comi said.

One patient in the placebo group developed pericarditis. There was no evidence of decreased immune function on laquinimod. For example, 17% on placebo on 20% on laquinimod developed herpes infection. There were six cases of cancer in the placebo group and eight in the laquinimod group, for rates of 1.1% and 1.5%, respectively.

A parallel trial is underway to confirm the findings, and results from that trial are expected in the fall of 2011, he said.

Teva Pharmaceuticals, which is developing laquinimod, funded the study. Dr. Comi has received compensation from Teva, Novartis, Sanofi-Aventis, Merck Serono, and Bayer Schering Pharma. Some of his associates in the study reported relationships with Teva and other companies manufacturing drugs for MS.

A parallel trial is underway to confirm the findings, and results from the trial are expected in the fall of 2011.

Source DR. COMI

View on The News

Drug Will Easily Find a Niche

The results were very positive on disease and on relapse rate reduction. These were both very good signs. In addition, laquinimod was a relatively or maybe very safe medication for people to take.

In contrast, some of the newer agents are having difficulty going through the phase III testing for approval. For example, one of the other agents has been held up in the Food and Drug Administration review because of safety concerns.

Another one that was just approved has risks for immune suppression. Laquinimod does not appear to have a risk for immune suppression, yet it has efficacy in relapsing-remitting MS.

Many patients who will tolerate one drug will not tolerate another drug, so it will be very easy to find a niche for this particular drug.

Most patients don't want an injectable therapy. On the other hand, we have to recognize that even an oral medication can pose some risks. Laquinimod does not seem to have any of those risks, but it causes immune modulation, so it may fit in early MS where it may show its greater efficacy.

What we've learned in the last 10 years – and most important of all – is not which drug to use, but when to treat, and to treat early, because treating early seems to be where we can see the best and most effect.

Laquinimod has a different mechanism of action. It seems to involve the signaling pathways that are in the innate immune system. We're learning about that now. There is going to be much more to be learned about this drug after it's approved in terms of its mechanisms of action.

SCOTT S. ZAMVIL, M.D., is professor of neurology at the University of California, San Francisco. He was not associated with the laquinimod study. He has been a consultant for Teva Pharmaceuticals, Biogen Idec, and Serono. In addition, Dr. Zamvil has received grant support or served on data safety monitoring boards for multiple drug companies.

HONOLULU – Two years of taking the investigational oral drug laquinimod reduced multiple sclerosis relapses and slowed progression toward disability and brain atrophy, compared with placebo, in a phase III study of 1,106 patients with relapsing-remitting multiple sclerosis.

The annualized relapse rate declined by 23% among patients who took laquinimod 0.6 mg daily in the randomized trial, which involved 139 centers in 24 countries, Dr. Giancarlo Comi and his associates reported at the meetingo The annualized relapse rates were 0.304 on laquinimod and 0.395 on placebo.

The laquinimod group also showed a 36% reduction in disability progression, which “is quite a big thing, more than what has been reported” in previous drug studies, said Dr. Comi, director of the department of neurology and the institute of experimental neurology at the Scientific Institute and University of Vita-Salute San Raffaele, Milan.

Most importantly, he said in an interview, the laquinimod group showed 33% less brain atrophy over the course of the study. “That's interesting because most drugs fail to have an effect on this,” he said.

These multiple benefits may be tied to laquinimod's novel mechanism of action, which addresses both the disease's acute inflammatory activity and the accumulation of irreversible tissue damage, he said.

The results suggest that laquinimod is a “very promising” treatment, Dr. Comi said. “In the end, what matters is how much damage there is to the patient and how much the drug was able to prevent that.”

Baseline characteristics of the two groups were similar, including demographics, clinical factors and MRI findings. At the start of the study, 46% of the laquinimod group and 40% of the placebo group had active disease. Patients in both groups had had MS for an average of 9 years.

Patients underwent clinical evaluations every 3 months and yearly MRI exams. By the end of the study, the mean number of gadolinium-enhanced lesions on MRI was 37% lower in the laquinimod group and the mean number of new T2 lesions was 30% lower, compared with placebo. The mean number of new T1 lesions, which are characterized by more severe tissue damage, was 27% lower with the drug, compared with placebo.

Laquinimod appeared to be well tolerated. Seventy-nine percent of patients who were randomized to laquinimod and 77% of patients who were randomized to placebo finished the double-blind study.

Elevations of liver enzymes were more common in the laquinimod group (7%) than in the placebo group (3%), but these were transient and reversible and did not lead to signs of liver problems, Dr. Comi said. Liver enzyme elevations greater than three times the upper limit of normal occurred in 2% of the placebo group and 5% of the laquinimod group.

The overall rates of adverse events were low (22% on laquinimod and 16% on placebo) and did not differ significantly between the drug and placebo groups. Two patients on placebo died from unrelated causes, with no deaths in the laquinimod group. The laquinimod group reported higher rates of abdominal pain (5%) and back pain (16%), compared with placebo (3% and 9%, respectively).

In 2010, the oral medication fingolimod (Gilenya) was approved as adjunctive therapy for relapsing-remitting MS. Concerns about increased risks for cardiac problems, immune suppression, and cancer with fingolimod were not a problem in the laquinimod study, Dr. Comi said.

One patient in the placebo group developed pericarditis. There was no evidence of decreased immune function on laquinimod. For example, 17% on placebo on 20% on laquinimod developed herpes infection. There were six cases of cancer in the placebo group and eight in the laquinimod group, for rates of 1.1% and 1.5%, respectively.

A parallel trial is underway to confirm the findings, and results from that trial are expected in the fall of 2011, he said.

Teva Pharmaceuticals, which is developing laquinimod, funded the study. Dr. Comi has received compensation from Teva, Novartis, Sanofi-Aventis, Merck Serono, and Bayer Schering Pharma. Some of his associates in the study reported relationships with Teva and other companies manufacturing drugs for MS.

A parallel trial is underway to confirm the findings, and results from the trial are expected in the fall of 2011.

Source DR. COMI

View on The News

Drug Will Easily Find a Niche

The results were very positive on disease and on relapse rate reduction. These were both very good signs. In addition, laquinimod was a relatively or maybe very safe medication for people to take.

In contrast, some of the newer agents are having difficulty going through the phase III testing for approval. For example, one of the other agents has been held up in the Food and Drug Administration review because of safety concerns.

Another one that was just approved has risks for immune suppression. Laquinimod does not appear to have a risk for immune suppression, yet it has efficacy in relapsing-remitting MS.

Many patients who will tolerate one drug will not tolerate another drug, so it will be very easy to find a niche for this particular drug.

Most patients don't want an injectable therapy. On the other hand, we have to recognize that even an oral medication can pose some risks. Laquinimod does not seem to have any of those risks, but it causes immune modulation, so it may fit in early MS where it may show its greater efficacy.

What we've learned in the last 10 years – and most important of all – is not which drug to use, but when to treat, and to treat early, because treating early seems to be where we can see the best and most effect.

Laquinimod has a different mechanism of action. It seems to involve the signaling pathways that are in the innate immune system. We're learning about that now. There is going to be much more to be learned about this drug after it's approved in terms of its mechanisms of action.

SCOTT S. ZAMVIL, M.D., is professor of neurology at the University of California, San Francisco. He was not associated with the laquinimod study. He has been a consultant for Teva Pharmaceuticals, Biogen Idec, and Serono. In addition, Dr. Zamvil has received grant support or served on data safety monitoring boards for multiple drug companies.

Vitamin D metabolism is associated with disability and lower brain parenchymal fraction in patients with MS.

Vitamin D metabolites have protective associations with disability and brain atrophy in patients with multiple sclerosis (MS), according to a study in the February issue of the Journal of Neurology, Neurosurgery, and Psychiatry. In particular, the results indicate strong associations for the 24, 25(OH)2VD3 metabolite, which has not been extensively investigated in patients with MS, reported Bianca Weinstock-Guttman, MD, of the Department of Neurology, State University of New York, Buffalo, and colleagues.

Dr. Weinstock-Guttman and colleagues evaluated the significance of vitamin D and its active metabolites in brain tissue injury and clinical disability in 193 patients with MS (152 women; mean age, 46.1; disease duration, 13.8 years). Serum levels of 25-hydroxyvitamin D3 (25(OH)VD3), 25-hydroxyvitamin D2 (25(OH)VD2), 1α, 25-dihydroxyvitamin D3 (1, 25(OH)2VD3), and 24(R),25-dihydroxyvitamin D3 (24, 25(OH)2VD3) were measured using a novel capillary liquid—chromatography—mass spectrometry method.

The investigators used the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS) to assess disability. MRI measures included T2 lesion volume, T1 lesion volume, and brain parenchymal fraction. The associations between deseasonalized levels of vitamin D metabolites and clinical and MRI measurements were assessed using regression analyses.

Dr. Weinstock-Guttman’s group found that lower deseasonalized levels of total 25(OH)VD, 25(OH)VD3, and 24, 25(OH)2VD3 were associated with a higher MSSS score. Similarly, lower deseasonalized levels of 24, 25(OH)2VD3 were associated with a higher EDSS score. Higher values of the 25(OH)VD3 to 24, 25(OH)2VD3 ratio were associated with a higher MSSS score and lower brain parenchymal fraction.

“Our µLC/MS/MS assay was important for enabling the systems pharmacology approach, which to our knowledge has not been used to investigate vitamin D metabolism in MS disease progression,” stated the researchers. “The low serum concentration of 1, 25 (OH)2VD3, low ionization efficiency and fragmentation patterns of vitamin D metabolites precluded sensitive detection by selected reactions monitoring. To obtain higher sensitivity, samples were derivatized with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD), which is specific for vitamin D metabolites, and the solid phase extraction step enabled loading of analytes extracted from a relatively high volume of sample into the µLC separation step. The method achieved sensitive and selective quantification of vitamin D metabolites in 0.2 ml of serum.”

Vitamin D metabolism is associated with disability and lower brain parenchymal fraction in patients with MS.

Vitamin D metabolites have protective associations with disability and brain atrophy in patients with multiple sclerosis (MS), according to a study in the February issue of the Journal of Neurology, Neurosurgery, and Psychiatry. In particular, the results indicate strong associations for the 24, 25(OH)2VD3 metabolite, which has not been extensively investigated in patients with MS, reported Bianca Weinstock-Guttman, MD, of the Department of Neurology, State University of New York, Buffalo, and colleagues.

Dr. Weinstock-Guttman and colleagues evaluated the significance of vitamin D and its active metabolites in brain tissue injury and clinical disability in 193 patients with MS (152 women; mean age, 46.1; disease duration, 13.8 years). Serum levels of 25-hydroxyvitamin D3 (25(OH)VD3), 25-hydroxyvitamin D2 (25(OH)VD2), 1α, 25-dihydroxyvitamin D3 (1, 25(OH)2VD3), and 24(R),25-dihydroxyvitamin D3 (24, 25(OH)2VD3) were measured using a novel capillary liquid—chromatography—mass spectrometry method.

The investigators used the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS) to assess disability. MRI measures included T2 lesion volume, T1 lesion volume, and brain parenchymal fraction. The associations between deseasonalized levels of vitamin D metabolites and clinical and MRI measurements were assessed using regression analyses.

Dr. Weinstock-Guttman’s group found that lower deseasonalized levels of total 25(OH)VD, 25(OH)VD3, and 24, 25(OH)2VD3 were associated with a higher MSSS score. Similarly, lower deseasonalized levels of 24, 25(OH)2VD3 were associated with a higher EDSS score. Higher values of the 25(OH)VD3 to 24, 25(OH)2VD3 ratio were associated with a higher MSSS score and lower brain parenchymal fraction.

“Our µLC/MS/MS assay was important for enabling the systems pharmacology approach, which to our knowledge has not been used to investigate vitamin D metabolism in MS disease progression,” stated the researchers. “The low serum concentration of 1, 25 (OH)2VD3, low ionization efficiency and fragmentation patterns of vitamin D metabolites precluded sensitive detection by selected reactions monitoring. To obtain higher sensitivity, samples were derivatized with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD), which is specific for vitamin D metabolites, and the solid phase extraction step enabled loading of analytes extracted from a relatively high volume of sample into the µLC separation step. The method achieved sensitive and selective quantification of vitamin D metabolites in 0.2 ml of serum.”

Vitamin D metabolism is associated with disability and lower brain parenchymal fraction in patients with MS.

Vitamin D metabolites have protective associations with disability and brain atrophy in patients with multiple sclerosis (MS), according to a study in the February issue of the Journal of Neurology, Neurosurgery, and Psychiatry. In particular, the results indicate strong associations for the 24, 25(OH)2VD3 metabolite, which has not been extensively investigated in patients with MS, reported Bianca Weinstock-Guttman, MD, of the Department of Neurology, State University of New York, Buffalo, and colleagues.

Dr. Weinstock-Guttman and colleagues evaluated the significance of vitamin D and its active metabolites in brain tissue injury and clinical disability in 193 patients with MS (152 women; mean age, 46.1; disease duration, 13.8 years). Serum levels of 25-hydroxyvitamin D3 (25(OH)VD3), 25-hydroxyvitamin D2 (25(OH)VD2), 1α, 25-dihydroxyvitamin D3 (1, 25(OH)2VD3), and 24(R),25-dihydroxyvitamin D3 (24, 25(OH)2VD3) were measured using a novel capillary liquid—chromatography—mass spectrometry method.

The investigators used the Expanded Disability Status Scale (EDSS) and the MS Severity Scale (MSSS) to assess disability. MRI measures included T2 lesion volume, T1 lesion volume, and brain parenchymal fraction. The associations between deseasonalized levels of vitamin D metabolites and clinical and MRI measurements were assessed using regression analyses.

Dr. Weinstock-Guttman’s group found that lower deseasonalized levels of total 25(OH)VD, 25(OH)VD3, and 24, 25(OH)2VD3 were associated with a higher MSSS score. Similarly, lower deseasonalized levels of 24, 25(OH)2VD3 were associated with a higher EDSS score. Higher values of the 25(OH)VD3 to 24, 25(OH)2VD3 ratio were associated with a higher MSSS score and lower brain parenchymal fraction.

“Our µLC/MS/MS assay was important for enabling the systems pharmacology approach, which to our knowledge has not been used to investigate vitamin D metabolism in MS disease progression,” stated the researchers. “The low serum concentration of 1, 25 (OH)2VD3, low ionization efficiency and fragmentation patterns of vitamin D metabolites precluded sensitive detection by selected reactions monitoring. To obtain higher sensitivity, samples were derivatized with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD), which is specific for vitamin D metabolites, and the solid phase extraction step enabled loading of analytes extracted from a relatively high volume of sample into the µLC separation step. The method achieved sensitive and selective quantification of vitamin D metabolites in 0.2 ml of serum.”

A second brain death examination in patients older than 1 year is largely unecessary and may negatively affect organ donation, according to a report in the January 11 online Neurology. “In practice, observation time to a second neurologic examination was three times longer than the proposed guideline and associated with substantial intensive care unit costs and loss of viable organs,” researchers stated. The investigators reviewed data for 1,229 adult and 82 pediatric patients who had been pronounced brain-dead. No patients who were declared brain-dead regained brainstem function after repeat examination. The mean brain death declaration interval between the two examinations was 19.2 hours. Consent for organ donation decreased from 57% to 45% as the brain death declaration interval increased. However, refusal of organ donation increased from 23% to 36% as the brain death interval increased. A total of 166 patients (12%) sustained a cardiac arrest between the two examinations or after the second examination.

Most antiepileptic drugs (AEDs) were associated with an increased risk of nontraumatic fractures in patients 50 and older, according to a study in the January Archives of Neurology. A total of 15,792 persons with nontraumatic fractures of the wrist, hip, and vertebra were analyzed. Each patient was matched for age, sex, ethnicity, and comorbidity with as many as three controls (n = 47,289). Prior AED use among participants included carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproic acid, and vigabatrin. The researchers found a significant increase in fracture risk for most of the AEDs (carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin). The adjusted odds ratios (ORs) ranged from 1.24 for clonazepam use to 1.91 for phenytoin use. Valproic acid (adjusted OR, 1.10) was the only AED not associated with an increased fracture risk. “Further studies are warranted to assess the risk of nontraumatic fractures with the newer AEDs and to determine the efficacy of osteoprotective medications in this population,” the researchers stated.

Although some pediatric patients with multiple sclerosis (MS) refractory to initial treatment may effectively switch between first-line disease-modifying therapies (DMTs), some may require second-line therapeutic interventions, per a report in the December 13, 2010, online Archives of Neurology. Researchers reviewed the records of 258 children with a confirmed diagnosis of MS and who had taken DMTs. Interferon beta and glatiramer acetate were the two most frequently used first-line DMTs. Overall, 144 children (55.8%) continued to receive one therapy, while 65 (25.2%) received two sequential therapies, 29 (11.2%) received three therapies, and 20 (7.8%) received four or more therapies during a mean observation period of 3.9 years. “Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%),” stated the investigators.

Transient pregnancy restless legs syndrome is a significant risk factor for developing a future chronic idiopathic restless legs syndrome form, and for a new transient symptomatology in a future pregnancy, according to a study in the December 7, 2010, Neurology. Seventy-four women who experienced restless legs syndrome during a previous pregnancy, and 133 who did not, were included in the study. The incidence of restless legs syndrome was 56% person/year in women who experienced the transient pregnancy restless legs syndrome form, versus 12.6% person/year in women who did not, with a significant fourfold increased risk of developing chronic restless legs syndrome in women who presented with restless legs syndrome in their previous pregnancy. “Considering further new pregnancies during the follow-up period, restless legs symptoms reappeared in 58% of the cases, while they emerged for the first time in only 3% of women who had never experienced restless legs syndrome,” stated the authors. 

The cancer drug paclitaxel may promote the regeneration of injured nerve cells in the CNS after spinal cord injury, according to a study in the online January 27 Science. Researchers found that the drug has a dual role in spinal cord repair in rodents, stabilizing the microtuble so that injured nerve cells regain their ability to grow and preventing the production of inhibitory substances in the scar tissue. Moderate microtubule stabilization decreased scar formation via various cellular mechanisms, including dampening of transforming growth factor-β signaling. “It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth competent sensory neurons,” stated the investigators. “Microtubule stabilization also promoted growth of CNS axons of the Raphe-spinal tract and led to functional improvement.”

Among patients with acute ischemic stroke, blacks have a lower mortality than whites, which may be attributable to differences in receiving life-sustaining interventions and end-of-life care, researchers reported in the February 1 Annals of Internal Medicine. The findings are based on 5,319 black and 18,340 white patients 18 and older who were hospitalized with acute ischemic stroke. The overall in-hospital mortality rate was lower for black patients than for white patients (5.0% vs 7.4%), as was all-cause mortality at 30 days (6.1% vs 11.4%) and one year (16.5% vs 24.4%). After propensity score adjustment, black race was independently associated with lower in-hospital mortality (odds ratio [OR], 0.77) and all-cause mortality up to one year (OR, 0.86). “After adjustment for the probability of dying in the hospital, black patients with stroke were more likely to receive life-sustaining interventions (OR, 1.22) but less likely to be discharged to hospice (OR, 0.25),” the researchers concluded.

A second brain death examination in patients older than 1 year is largely unecessary and may negatively affect organ donation, according to a report in the January 11 online Neurology. “In practice, observation time to a second neurologic examination was three times longer than the proposed guideline and associated with substantial intensive care unit costs and loss of viable organs,” researchers stated. The investigators reviewed data for 1,229 adult and 82 pediatric patients who had been pronounced brain-dead. No patients who were declared brain-dead regained brainstem function after repeat examination. The mean brain death declaration interval between the two examinations was 19.2 hours. Consent for organ donation decreased from 57% to 45% as the brain death declaration interval increased. However, refusal of organ donation increased from 23% to 36% as the brain death interval increased. A total of 166 patients (12%) sustained a cardiac arrest between the two examinations or after the second examination.

Most antiepileptic drugs (AEDs) were associated with an increased risk of nontraumatic fractures in patients 50 and older, according to a study in the January Archives of Neurology. A total of 15,792 persons with nontraumatic fractures of the wrist, hip, and vertebra were analyzed. Each patient was matched for age, sex, ethnicity, and comorbidity with as many as three controls (n = 47,289). Prior AED use among participants included carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproic acid, and vigabatrin. The researchers found a significant increase in fracture risk for most of the AEDs (carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin). The adjusted odds ratios (ORs) ranged from 1.24 for clonazepam use to 1.91 for phenytoin use. Valproic acid (adjusted OR, 1.10) was the only AED not associated with an increased fracture risk. “Further studies are warranted to assess the risk of nontraumatic fractures with the newer AEDs and to determine the efficacy of osteoprotective medications in this population,” the researchers stated.

Although some pediatric patients with multiple sclerosis (MS) refractory to initial treatment may effectively switch between first-line disease-modifying therapies (DMTs), some may require second-line therapeutic interventions, per a report in the December 13, 2010, online Archives of Neurology. Researchers reviewed the records of 258 children with a confirmed diagnosis of MS and who had taken DMTs. Interferon beta and glatiramer acetate were the two most frequently used first-line DMTs. Overall, 144 children (55.8%) continued to receive one therapy, while 65 (25.2%) received two sequential therapies, 29 (11.2%) received three therapies, and 20 (7.8%) received four or more therapies during a mean observation period of 3.9 years. “Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%),” stated the investigators.

Transient pregnancy restless legs syndrome is a significant risk factor for developing a future chronic idiopathic restless legs syndrome form, and for a new transient symptomatology in a future pregnancy, according to a study in the December 7, 2010, Neurology. Seventy-four women who experienced restless legs syndrome during a previous pregnancy, and 133 who did not, were included in the study. The incidence of restless legs syndrome was 56% person/year in women who experienced the transient pregnancy restless legs syndrome form, versus 12.6% person/year in women who did not, with a significant fourfold increased risk of developing chronic restless legs syndrome in women who presented with restless legs syndrome in their previous pregnancy. “Considering further new pregnancies during the follow-up period, restless legs symptoms reappeared in 58% of the cases, while they emerged for the first time in only 3% of women who had never experienced restless legs syndrome,” stated the authors. 

The cancer drug paclitaxel may promote the regeneration of injured nerve cells in the CNS after spinal cord injury, according to a study in the online January 27 Science. Researchers found that the drug has a dual role in spinal cord repair in rodents, stabilizing the microtuble so that injured nerve cells regain their ability to grow and preventing the production of inhibitory substances in the scar tissue. Moderate microtubule stabilization decreased scar formation via various cellular mechanisms, including dampening of transforming growth factor-β signaling. “It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth competent sensory neurons,” stated the investigators. “Microtubule stabilization also promoted growth of CNS axons of the Raphe-spinal tract and led to functional improvement.”

Among patients with acute ischemic stroke, blacks have a lower mortality than whites, which may be attributable to differences in receiving life-sustaining interventions and end-of-life care, researchers reported in the February 1 Annals of Internal Medicine. The findings are based on 5,319 black and 18,340 white patients 18 and older who were hospitalized with acute ischemic stroke. The overall in-hospital mortality rate was lower for black patients than for white patients (5.0% vs 7.4%), as was all-cause mortality at 30 days (6.1% vs 11.4%) and one year (16.5% vs 24.4%). After propensity score adjustment, black race was independently associated with lower in-hospital mortality (odds ratio [OR], 0.77) and all-cause mortality up to one year (OR, 0.86). “After adjustment for the probability of dying in the hospital, black patients with stroke were more likely to receive life-sustaining interventions (OR, 1.22) but less likely to be discharged to hospice (OR, 0.25),” the researchers concluded.

A second brain death examination in patients older than 1 year is largely unecessary and may negatively affect organ donation, according to a report in the January 11 online Neurology. “In practice, observation time to a second neurologic examination was three times longer than the proposed guideline and associated with substantial intensive care unit costs and loss of viable organs,” researchers stated. The investigators reviewed data for 1,229 adult and 82 pediatric patients who had been pronounced brain-dead. No patients who were declared brain-dead regained brainstem function after repeat examination. The mean brain death declaration interval between the two examinations was 19.2 hours. Consent for organ donation decreased from 57% to 45% as the brain death declaration interval increased. However, refusal of organ donation increased from 23% to 36% as the brain death interval increased. A total of 166 patients (12%) sustained a cardiac arrest between the two examinations or after the second examination.

Most antiepileptic drugs (AEDs) were associated with an increased risk of nontraumatic fractures in patients 50 and older, according to a study in the January Archives of Neurology. A total of 15,792 persons with nontraumatic fractures of the wrist, hip, and vertebra were analyzed. Each patient was matched for age, sex, ethnicity, and comorbidity with as many as three controls (n = 47,289). Prior AED use among participants included carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproic acid, and vigabatrin. The researchers found a significant increase in fracture risk for most of the AEDs (carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin). The adjusted odds ratios (ORs) ranged from 1.24 for clonazepam use to 1.91 for phenytoin use. Valproic acid (adjusted OR, 1.10) was the only AED not associated with an increased fracture risk. “Further studies are warranted to assess the risk of nontraumatic fractures with the newer AEDs and to determine the efficacy of osteoprotective medications in this population,” the researchers stated.

Although some pediatric patients with multiple sclerosis (MS) refractory to initial treatment may effectively switch between first-line disease-modifying therapies (DMTs), some may require second-line therapeutic interventions, per a report in the December 13, 2010, online Archives of Neurology. Researchers reviewed the records of 258 children with a confirmed diagnosis of MS and who had taken DMTs. Interferon beta and glatiramer acetate were the two most frequently used first-line DMTs. Overall, 144 children (55.8%) continued to receive one therapy, while 65 (25.2%) received two sequential therapies, 29 (11.2%) received three therapies, and 20 (7.8%) received four or more therapies during a mean observation period of 3.9 years. “Second-line DMT use was restricted to interferon beta and glatiramer acetate in 203 children (78.7%), whereas other treatments such as broad-spectrum chemotherapies (cyclophosphamide, mitoxantrone hydrochloride), natalizumab, corticosteroids (monthly), and daclizumab were used at some point during the observation period for disease management in 55 children (21.3%),” stated the investigators.

Transient pregnancy restless legs syndrome is a significant risk factor for developing a future chronic idiopathic restless legs syndrome form, and for a new transient symptomatology in a future pregnancy, according to a study in the December 7, 2010, Neurology. Seventy-four women who experienced restless legs syndrome during a previous pregnancy, and 133 who did not, were included in the study. The incidence of restless legs syndrome was 56% person/year in women who experienced the transient pregnancy restless legs syndrome form, versus 12.6% person/year in women who did not, with a significant fourfold increased risk of developing chronic restless legs syndrome in women who presented with restless legs syndrome in their previous pregnancy. “Considering further new pregnancies during the follow-up period, restless legs symptoms reappeared in 58% of the cases, while they emerged for the first time in only 3% of women who had never experienced restless legs syndrome,” stated the authors. 

The cancer drug paclitaxel may promote the regeneration of injured nerve cells in the CNS after spinal cord injury, according to a study in the online January 27 Science. Researchers found that the drug has a dual role in spinal cord repair in rodents, stabilizing the microtuble so that injured nerve cells regain their ability to grow and preventing the production of inhibitory substances in the scar tissue. Moderate microtubule stabilization decreased scar formation via various cellular mechanisms, including dampening of transforming growth factor-β signaling. “It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth competent sensory neurons,” stated the investigators. “Microtubule stabilization also promoted growth of CNS axons of the Raphe-spinal tract and led to functional improvement.”

Among patients with acute ischemic stroke, blacks have a lower mortality than whites, which may be attributable to differences in receiving life-sustaining interventions and end-of-life care, researchers reported in the February 1 Annals of Internal Medicine. The findings are based on 5,319 black and 18,340 white patients 18 and older who were hospitalized with acute ischemic stroke. The overall in-hospital mortality rate was lower for black patients than for white patients (5.0% vs 7.4%), as was all-cause mortality at 30 days (6.1% vs 11.4%) and one year (16.5% vs 24.4%). After propensity score adjustment, black race was independently associated with lower in-hospital mortality (odds ratio [OR], 0.77) and all-cause mortality up to one year (OR, 0.86). “After adjustment for the probability of dying in the hospital, black patients with stroke were more likely to receive life-sustaining interventions (OR, 1.22) but less likely to be discharged to hospice (OR, 0.25),” the researchers concluded.