ICYMI Multiple Sclerosis

Olfactory bulb and brain volume may provide valuable information about olfactory dysfunction in patients with MS.

HONOLULU—A correlation between decreased olfactory bulb and brain volume and multiple sclerosis (MS) lesions may help to explain olfactory dysfunction among patients with MS, according to research presented at the American Academy of Neurology’s 63rd Annual Meeting.

Noting that olfactory dysfunction can occur in patients with MS, Felix Alexander Schmidt, a medical student at the Department of Neurology, University Hospitals Charité in Berlin, and colleagues investigated the reasons for the problem and the best ways of detecting it. They determined and compared objective olfactometry, olfactory bulb volume, olfactory brain volume, and number and volume of lesions in the olfactory brain in patients with MS.

Their study, which was also published in the May 17 online PLoS One, included 34 patients (24 women), ages 22 to 64, with MS and 30 healthy controls matched by age, sex, and smoking habits. Participants’ olfactory bulb volume, olfactory brain volume, and plaque load were assessed with use of MRI. The researchers performed orthonasal olfactory testing using the Threshold-Discrimination-Identification test, and they determined objective olfactometry by measuring Olfactory-Evoked-Potentials. Participants also were given the Expanded Disability Status Scale (EDSS) test.

Olfactory dysfunction was present in 41% of patients with MS and 8% of the control group. The researchers found hyposmia in 71% of patients with a decreased olfactory bulb volume (<100 mm3) and 83% of patients with a decreased olfactory brain volume (<30,000 mm3). Decreased olfactory bulb volume was correlated with objective olfactometry, as well as with the number and volume of MS lesions in the olfactory brain. In addition, decreased olfactory brain volume was correlated with the volume of lesions in the olfactory brain and EDSS scores. Patients’ scores on the Identification subtest of the Threshold-Discrimination-Identification test were correlated with their EDSS scores, latest relapsing phase, and disease duration.

“The correlation between a higher number and volume of lesions in the olfactory brain with a decreased olfactory bulb and olfactory brain volume could help to explain olfactory dysfunction in MS patients,” the researchers concluded. “The correlation between volumetric measurements and objective olfactometry results shows that olfactory bulb and olfactory brain volume may provide valuable information about olfactory function in MS patients. Hyposmia seems to appear more frequently in an early stage of disease. The Identification subtest was especially sensitive in detecting olfactory changes in MS patients.”

Olfactory bulb and brain volume may provide valuable information about olfactory dysfunction in patients with MS.

HONOLULU—A correlation between decreased olfactory bulb and brain volume and multiple sclerosis (MS) lesions may help to explain olfactory dysfunction among patients with MS, according to research presented at the American Academy of Neurology’s 63rd Annual Meeting.

Noting that olfactory dysfunction can occur in patients with MS, Felix Alexander Schmidt, a medical student at the Department of Neurology, University Hospitals Charité in Berlin, and colleagues investigated the reasons for the problem and the best ways of detecting it. They determined and compared objective olfactometry, olfactory bulb volume, olfactory brain volume, and number and volume of lesions in the olfactory brain in patients with MS.

Their study, which was also published in the May 17 online PLoS One, included 34 patients (24 women), ages 22 to 64, with MS and 30 healthy controls matched by age, sex, and smoking habits. Participants’ olfactory bulb volume, olfactory brain volume, and plaque load were assessed with use of MRI. The researchers performed orthonasal olfactory testing using the Threshold-Discrimination-Identification test, and they determined objective olfactometry by measuring Olfactory-Evoked-Potentials. Participants also were given the Expanded Disability Status Scale (EDSS) test.

Olfactory dysfunction was present in 41% of patients with MS and 8% of the control group. The researchers found hyposmia in 71% of patients with a decreased olfactory bulb volume (<100 mm3) and 83% of patients with a decreased olfactory brain volume (<30,000 mm3). Decreased olfactory bulb volume was correlated with objective olfactometry, as well as with the number and volume of MS lesions in the olfactory brain. In addition, decreased olfactory brain volume was correlated with the volume of lesions in the olfactory brain and EDSS scores. Patients’ scores on the Identification subtest of the Threshold-Discrimination-Identification test were correlated with their EDSS scores, latest relapsing phase, and disease duration.

“The correlation between a higher number and volume of lesions in the olfactory brain with a decreased olfactory bulb and olfactory brain volume could help to explain olfactory dysfunction in MS patients,” the researchers concluded. “The correlation between volumetric measurements and objective olfactometry results shows that olfactory bulb and olfactory brain volume may provide valuable information about olfactory function in MS patients. Hyposmia seems to appear more frequently in an early stage of disease. The Identification subtest was especially sensitive in detecting olfactory changes in MS patients.”

Olfactory bulb and brain volume may provide valuable information about olfactory dysfunction in patients with MS.

HONOLULU—A correlation between decreased olfactory bulb and brain volume and multiple sclerosis (MS) lesions may help to explain olfactory dysfunction among patients with MS, according to research presented at the American Academy of Neurology’s 63rd Annual Meeting.

Noting that olfactory dysfunction can occur in patients with MS, Felix Alexander Schmidt, a medical student at the Department of Neurology, University Hospitals Charité in Berlin, and colleagues investigated the reasons for the problem and the best ways of detecting it. They determined and compared objective olfactometry, olfactory bulb volume, olfactory brain volume, and number and volume of lesions in the olfactory brain in patients with MS.

Their study, which was also published in the May 17 online PLoS One, included 34 patients (24 women), ages 22 to 64, with MS and 30 healthy controls matched by age, sex, and smoking habits. Participants’ olfactory bulb volume, olfactory brain volume, and plaque load were assessed with use of MRI. The researchers performed orthonasal olfactory testing using the Threshold-Discrimination-Identification test, and they determined objective olfactometry by measuring Olfactory-Evoked-Potentials. Participants also were given the Expanded Disability Status Scale (EDSS) test.

Olfactory dysfunction was present in 41% of patients with MS and 8% of the control group. The researchers found hyposmia in 71% of patients with a decreased olfactory bulb volume (<100 mm3) and 83% of patients with a decreased olfactory brain volume (<30,000 mm3). Decreased olfactory bulb volume was correlated with objective olfactometry, as well as with the number and volume of MS lesions in the olfactory brain. In addition, decreased olfactory brain volume was correlated with the volume of lesions in the olfactory brain and EDSS scores. Patients’ scores on the Identification subtest of the Threshold-Discrimination-Identification test were correlated with their EDSS scores, latest relapsing phase, and disease duration.

“The correlation between a higher number and volume of lesions in the olfactory brain with a decreased olfactory bulb and olfactory brain volume could help to explain olfactory dysfunction in MS patients,” the researchers concluded. “The correlation between volumetric measurements and objective olfactometry results shows that olfactory bulb and olfactory brain volume may provide valuable information about olfactory function in MS patients. Hyposmia seems to appear more frequently in an early stage of disease. The Identification subtest was especially sensitive in detecting olfactory changes in MS patients.”

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.

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.

Depression, fatigue, and lack of physical activity are associated with decreased bone mineral density in patients with MS and replete vitamin D level, researchers report. 

In ambulatory patients with multiple sclerosis (MS) who have adequate vitamin D stores, depression, fatigue, and a lack of moderate physical activity are associated with decreased femoral and lumbar bone mineral density, according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
Alexander Ng, PhD, Associate Professor of Exercise Science, Marquette University, Milwaukee, and colleagues examined 23 patients with MS and 22 healthy controls. Study participants underwent Dual Energy X-ray Absorptiometry (DEXA) of femoral, neck, lumbar, and total body, and resting supine EKGs. In addition, data were collected with use of the MS Functional Composite Measure, Expanded Disability Status Scale (EDSS), Fatigue Impact Scale, and Beck Depression Inventory, and levels of salivary cortisol and serum vitamin D were measured.
Depression and Fatigue in Patients With MS
The researchers found that patients with MS reported greater levels of depression and fatigue than did controls, and subjects also had lower MS Functional Composite Measure scores. No differences were observed between subjects and controls in measures of vitamin D, cortisol, mineral bone density, or heart rate variability.
Levels of moderate but not total physical activity differed between the two groups. Moderate activity was directly correlated to femoral bone mineral density in the MS group, but not in controls. EDSS also correlated to femoral bone mineral density. Depression and fatigue both correlated with femoral and lumbar bone mineral density in the MS group but not in controls.
“Young women and men with MS are at an increased risk for decreased bone mineral density, which, if combined with decreased balance, could lead to an increased risk of bone fractures due to falling or otherwise,” Dr. Ng told Neurology Reviews.
“Appropriate weight-bearing exercise of moderate intensity in persons with MS could be an effective nonpharmacologic countermeasure to this bone mineral density risk,” he added.
The Benefits of Exercise
"Exercise is already recommended for persons with MS for fitness and health risk reduction,” he continued. “Maintaining or increasing bone density is yet another potential benefit of exercise for persons with MS. Intense or hard exercise may not be necessary to improve bone mineral density, although easy exercise may not provide enough of an osteogenic stimulus.”

Depression, fatigue, and lack of physical activity are associated with decreased bone mineral density in patients with MS and replete vitamin D level, researchers report. 

In ambulatory patients with multiple sclerosis (MS) who have adequate vitamin D stores, depression, fatigue, and a lack of moderate physical activity are associated with decreased femoral and lumbar bone mineral density, according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
Alexander Ng, PhD, Associate Professor of Exercise Science, Marquette University, Milwaukee, and colleagues examined 23 patients with MS and 22 healthy controls. Study participants underwent Dual Energy X-ray Absorptiometry (DEXA) of femoral, neck, lumbar, and total body, and resting supine EKGs. In addition, data were collected with use of the MS Functional Composite Measure, Expanded Disability Status Scale (EDSS), Fatigue Impact Scale, and Beck Depression Inventory, and levels of salivary cortisol and serum vitamin D were measured.
Depression and Fatigue in Patients With MS
The researchers found that patients with MS reported greater levels of depression and fatigue than did controls, and subjects also had lower MS Functional Composite Measure scores. No differences were observed between subjects and controls in measures of vitamin D, cortisol, mineral bone density, or heart rate variability.
Levels of moderate but not total physical activity differed between the two groups. Moderate activity was directly correlated to femoral bone mineral density in the MS group, but not in controls. EDSS also correlated to femoral bone mineral density. Depression and fatigue both correlated with femoral and lumbar bone mineral density in the MS group but not in controls.
“Young women and men with MS are at an increased risk for decreased bone mineral density, which, if combined with decreased balance, could lead to an increased risk of bone fractures due to falling or otherwise,” Dr. Ng told Neurology Reviews.
“Appropriate weight-bearing exercise of moderate intensity in persons with MS could be an effective nonpharmacologic countermeasure to this bone mineral density risk,” he added.
The Benefits of Exercise
"Exercise is already recommended for persons with MS for fitness and health risk reduction,” he continued. “Maintaining or increasing bone density is yet another potential benefit of exercise for persons with MS. Intense or hard exercise may not be necessary to improve bone mineral density, although easy exercise may not provide enough of an osteogenic stimulus.”

Depression, fatigue, and lack of physical activity are associated with decreased bone mineral density in patients with MS and replete vitamin D level, researchers report. 

In ambulatory patients with multiple sclerosis (MS) who have adequate vitamin D stores, depression, fatigue, and a lack of moderate physical activity are associated with decreased femoral and lumbar bone mineral density, according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.
Alexander Ng, PhD, Associate Professor of Exercise Science, Marquette University, Milwaukee, and colleagues examined 23 patients with MS and 22 healthy controls. Study participants underwent Dual Energy X-ray Absorptiometry (DEXA) of femoral, neck, lumbar, and total body, and resting supine EKGs. In addition, data were collected with use of the MS Functional Composite Measure, Expanded Disability Status Scale (EDSS), Fatigue Impact Scale, and Beck Depression Inventory, and levels of salivary cortisol and serum vitamin D were measured.
Depression and Fatigue in Patients With MS
The researchers found that patients with MS reported greater levels of depression and fatigue than did controls, and subjects also had lower MS Functional Composite Measure scores. No differences were observed between subjects and controls in measures of vitamin D, cortisol, mineral bone density, or heart rate variability.
Levels of moderate but not total physical activity differed between the two groups. Moderate activity was directly correlated to femoral bone mineral density in the MS group, but not in controls. EDSS also correlated to femoral bone mineral density. Depression and fatigue both correlated with femoral and lumbar bone mineral density in the MS group but not in controls.
“Young women and men with MS are at an increased risk for decreased bone mineral density, which, if combined with decreased balance, could lead to an increased risk of bone fractures due to falling or otherwise,” Dr. Ng told Neurology Reviews.
“Appropriate weight-bearing exercise of moderate intensity in persons with MS could be an effective nonpharmacologic countermeasure to this bone mineral density risk,” he added.
The Benefits of Exercise
"Exercise is already recommended for persons with MS for fitness and health risk reduction,” he continued. “Maintaining or increasing bone density is yet another potential benefit of exercise for persons with MS. Intense or hard exercise may not be necessary to improve bone mineral density, although easy exercise may not provide enough of an osteogenic stimulus.”

Pregnancy and breastfeeding are strongly associated with low vitamin D levels in women with MS, but these low vitamin D levels are not associated with an increased risk of postpartum MS relapses.

Women with multiple sclerosis (MS) have lower vitamin D levels during pregnancy and while breastfeeding; however, according to a November 8 online report released by the Archives of Neurology, these low vitamin D levels were not associated with a greater risk of MS relapse postpartum.  
“During the last decade, low level of vitamin D, a potent immunomodulator, has emerged as an important risk factor for MS as well as other autoimmune diseases and certain cancers,” said Annette Langer-Gould, MD, PhD, and colleagues. “The observation that healthy pregnant and lactating women are at particularly high risk of vitamin D insufficiency, regardless of race, suggests that pregnant and nursing mothers with MS may have a higher risk of relapses.” However, they pointed out, it has already been well established that the risk of MS relapse decreases during pregnancy and increases during the postpartum period and that breastfeeding does not increase the risk of relapses.
Dr. Langer-Gould, at the time of the study at Stanford University School of Medicine and now at Kaiser Permanente Southern California’s Department of Research and Evaluation in Pasadena, and colleagues studied 28 pregnant women with MS identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics. Participants donated blood and completed questionnaires at the beginning of the study, during their remaining trimesters of pregnancy, and regularly through the first year after birth.
Fluctuating Vitamin D Levels
Of the 28 women, 14 (50%) breastfed exclusively and 12 (43%) relapsed within six months after giving birth. During pregnancy, average blood levels of 25-hydroxyvitamin D (25[OH]D) were 25.4 ng/mL and were associated with season. After birth, levels remained low among women who were exclusively breastfeeding but rose significantly in the nonexclusive breastfeeding group regardless of season. By four and six months after childbirth, 25(OH)D levels were an average of 5 ng/mL lower among women who breastfed exclusively than among those who did not. However, these low postpartum vitamin D levels were not associated with risk of MS relapse. “If anything, by three to six months after childbirth, 25(OH)D levels were marginally higher among the women who relapsed within the first six months after childbirth compared with women who were relapse-free during the same period,” the researchers said. “We do not believe that higher vitamin D levels increase the risk of postpartum relapses, as the rise we observed did not appear to occur prior to the onset of symptoms and the findings were of marginal statistical significance after accounting for season. Instead, we think this apparent inverse association is a reflection of the fact that most of the women who relapsed in the study also did not breastfeed or did so only briefly.”
The Bottom Line for Women With MS
“Our finding that low vitamin D is not a risk factor for MS relapse in pregnant and lactating women suggests that increasing vitamin D levels during pregnancy and the postpartum period in women with MS is unlikely to affect the risk of postpartum relapse,” the researchers concluded. “Therefore, our findings imply that the recommended dose of vitamin D supplementation for women with MS during pregnancy and lactation should be the same as for women who are not.”

Pregnancy and breastfeeding are strongly associated with low vitamin D levels in women with MS, but these low vitamin D levels are not associated with an increased risk of postpartum MS relapses.

Women with multiple sclerosis (MS) have lower vitamin D levels during pregnancy and while breastfeeding; however, according to a November 8 online report released by the Archives of Neurology, these low vitamin D levels were not associated with a greater risk of MS relapse postpartum.  
“During the last decade, low level of vitamin D, a potent immunomodulator, has emerged as an important risk factor for MS as well as other autoimmune diseases and certain cancers,” said Annette Langer-Gould, MD, PhD, and colleagues. “The observation that healthy pregnant and lactating women are at particularly high risk of vitamin D insufficiency, regardless of race, suggests that pregnant and nursing mothers with MS may have a higher risk of relapses.” However, they pointed out, it has already been well established that the risk of MS relapse decreases during pregnancy and increases during the postpartum period and that breastfeeding does not increase the risk of relapses.
Dr. Langer-Gould, at the time of the study at Stanford University School of Medicine and now at Kaiser Permanente Southern California’s Department of Research and Evaluation in Pasadena, and colleagues studied 28 pregnant women with MS identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics. Participants donated blood and completed questionnaires at the beginning of the study, during their remaining trimesters of pregnancy, and regularly through the first year after birth.
Fluctuating Vitamin D Levels
Of the 28 women, 14 (50%) breastfed exclusively and 12 (43%) relapsed within six months after giving birth. During pregnancy, average blood levels of 25-hydroxyvitamin D (25[OH]D) were 25.4 ng/mL and were associated with season. After birth, levels remained low among women who were exclusively breastfeeding but rose significantly in the nonexclusive breastfeeding group regardless of season. By four and six months after childbirth, 25(OH)D levels were an average of 5 ng/mL lower among women who breastfed exclusively than among those who did not. However, these low postpartum vitamin D levels were not associated with risk of MS relapse. “If anything, by three to six months after childbirth, 25(OH)D levels were marginally higher among the women who relapsed within the first six months after childbirth compared with women who were relapse-free during the same period,” the researchers said. “We do not believe that higher vitamin D levels increase the risk of postpartum relapses, as the rise we observed did not appear to occur prior to the onset of symptoms and the findings were of marginal statistical significance after accounting for season. Instead, we think this apparent inverse association is a reflection of the fact that most of the women who relapsed in the study also did not breastfeed or did so only briefly.”
The Bottom Line for Women With MS
“Our finding that low vitamin D is not a risk factor for MS relapse in pregnant and lactating women suggests that increasing vitamin D levels during pregnancy and the postpartum period in women with MS is unlikely to affect the risk of postpartum relapse,” the researchers concluded. “Therefore, our findings imply that the recommended dose of vitamin D supplementation for women with MS during pregnancy and lactation should be the same as for women who are not.”

Pregnancy and breastfeeding are strongly associated with low vitamin D levels in women with MS, but these low vitamin D levels are not associated with an increased risk of postpartum MS relapses.

Women with multiple sclerosis (MS) have lower vitamin D levels during pregnancy and while breastfeeding; however, according to a November 8 online report released by the Archives of Neurology, these low vitamin D levels were not associated with a greater risk of MS relapse postpartum.  
“During the last decade, low level of vitamin D, a potent immunomodulator, has emerged as an important risk factor for MS as well as other autoimmune diseases and certain cancers,” said Annette Langer-Gould, MD, PhD, and colleagues. “The observation that healthy pregnant and lactating women are at particularly high risk of vitamin D insufficiency, regardless of race, suggests that pregnant and nursing mothers with MS may have a higher risk of relapses.” However, they pointed out, it has already been well established that the risk of MS relapse decreases during pregnancy and increases during the postpartum period and that breastfeeding does not increase the risk of relapses.
Dr. Langer-Gould, at the time of the study at Stanford University School of Medicine and now at Kaiser Permanente Southern California’s Department of Research and Evaluation in Pasadena, and colleagues studied 28 pregnant women with MS identified through membership records of Kaiser Permanente Northern California or Stanford University outpatient neurology clinics. Participants donated blood and completed questionnaires at the beginning of the study, during their remaining trimesters of pregnancy, and regularly through the first year after birth.
Fluctuating Vitamin D Levels
Of the 28 women, 14 (50%) breastfed exclusively and 12 (43%) relapsed within six months after giving birth. During pregnancy, average blood levels of 25-hydroxyvitamin D (25[OH]D) were 25.4 ng/mL and were associated with season. After birth, levels remained low among women who were exclusively breastfeeding but rose significantly in the nonexclusive breastfeeding group regardless of season. By four and six months after childbirth, 25(OH)D levels were an average of 5 ng/mL lower among women who breastfed exclusively than among those who did not. However, these low postpartum vitamin D levels were not associated with risk of MS relapse. “If anything, by three to six months after childbirth, 25(OH)D levels were marginally higher among the women who relapsed within the first six months after childbirth compared with women who were relapse-free during the same period,” the researchers said. “We do not believe that higher vitamin D levels increase the risk of postpartum relapses, as the rise we observed did not appear to occur prior to the onset of symptoms and the findings were of marginal statistical significance after accounting for season. Instead, we think this apparent inverse association is a reflection of the fact that most of the women who relapsed in the study also did not breastfeed or did so only briefly.”
The Bottom Line for Women With MS
“Our finding that low vitamin D is not a risk factor for MS relapse in pregnant and lactating women suggests that increasing vitamin D levels during pregnancy and the postpartum period in women with MS is unlikely to affect the risk of postpartum relapse,” the researchers concluded. “Therefore, our findings imply that the recommended dose of vitamin D supplementation for women with MS during pregnancy and lactation should be the same as for women who are not.”

Findings support a pathogenic role for an autoantibody of AQP4 specificity in neuromyelitis optica.

SAN FRANCISCO—A complement activating aquaporin-4 (AQP4)-specific autoantibody has a pathogenic role in initiating neuromyelitis optica (NMO) lesions and distinguishes NMO from multiple sclerosis (MS), according to research presented at the 135th Annual Meeting of the American Neurological Association.
Clinical presentation of NMO differs from MS in a number of ways, explained Claudia Lucchinetti, MD, of the Mayo Clinic Rochester in Minnesota, and member of the Mayo Clinic NMO Consortium. NMO onset tends to occur at an older age, affects more females than males, and is more common in non-Caucasians. NMO is typically a relapsing disease, and unlike MS, a progressive course is distinctly unusual. In contrast to MS, brain MRI scans are often normal early in the disease, while spinal cord MRIs typically show long lesions spanning three or more intervertebral segments, which are not typically seen in adult MS. Oligoclonal bands in the spinal fluid are rare in NMO, whereas pleocytosis is common. NMO can be associated with other autoimmune disorders, including myasthenia gravis. Patients with active NMO respond favorably to antibody-depleting therapies.
In 2002, Dr. Lucchinetti and colleagues described the presence of deposits of immunoglobulin G (IgG) and immunoglobulin M (IgM) co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels in active NMO lesions, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. In 2004, Vanda Lennon, MD, PhD, and colleagues at the Mayo Clinic reported a specific serum autoantibody marker that was 73% sensitive and more than 90% specific for clinically defined NMO. Its selective binding to the abluminal face of microvessels, pia, subpia and Virchow-Robin sheaths was reminiscent of the localization of immune complexes in NMO patients’ spinal cord tissues described by Lucchinetti and colleagues.
“With the discovery of the biomarker, a spectrum of neurologic disorders has been identified associated with the presence of NMO-IgG, including not only NMO, but also isolated or recurrent longitudinally extensive transverse myelitis, or optic neuritis, encephalopathy, intractable nausea and vomiting, a posterior reversible leukoencephalopathy (PRES)-like syndrome, endocrinopathies, and even narcolepsy,” she said.
Aquaporin-4
Subsequent studies led by Dr. Lennon identified AQP4 as the target auto-antigen in NMO. AQP4 is the dominant CNS water channel, which regulates bidirectional water flux between the blood and brain, and the brain and spinal fluid, and is concentrated at the astrocytic end-feet. It is expressed in two isoforms, M1 and M23, and consists of six membranes that determine the channel’s selectivity for water molecules, Dr. Lucchinetti said.
AQP4 is found on the surfaces of astrocytes, concentrated in periventricular regions, circumventricular organs, and spinal cord gray matter in healthy controls. Normal AQP4 expression parallels the classic ring and rosette staining pattern of immune complex deposition observed in active NMO lesions. In contrast to active MS lesions, which show an increase in AQP4 immunoreactivity, NMO lesions show a striking loss of AQP4, she explained. “Interestingly, myelin may be relatively preserved in some of these lesions, despite the profound loss of AQP4,” said Dr. Lucchinetti.
Brain Lesions in NMO
MRI detects brain lesions in 60% of NMO patients, which include NMO-specific brain lesions in regions of high AQP4 expression (eg, area postrema, hypothalamus), as well as supratentorial lesions that are either nonspecific or MS-like in appearance. The presence of these supratentorial brain lesions has suggested a possible pathologic overlap of NMO and MS. However, comparison of supratentorial (ST) NMO lesions with opticospinal (OS) NMO lesions, as well as supratentorial MS lesions, confirmed that the pathology of NMO ST lesions is similar to NMO OS lesions with respect to type of inflammation, presence of perivascular immune complex deposits and AQP4 loss. Dr. Lucchinetti suggests these findings indicate that NMO ST and OS lesions have a shared pathogenesis.
Clinical reports have also described intractable hiccups, nausea, and vomiting in NMO. NMO specific medullary lesions have been observed in the area postrema, which are characterized by a selective and targeted loss of AQP4, and likely reflect the pathologic substrate of intractable nausea and vomiting reported in some NMO patients. A study in press by members of the Mayo Clinic NMO consortium suggests that the area postrema may even be the first point of attack in NMO in at least 12% of NMO cases, Dr. Lucchinetti reported.
The Role of NMO IgG
In vitro studies demonstrate that NMO-IgG binds selectively to the surface of living target cell membranes expressing AQP4, a prerequisite for IgG to affect organ-specific pathogenicity. This binding initiates two potentially competing outcomes: 1) rapid downregulation of AQP4 via endocytosis/degradation; and 2) activation of the lytic complement cascade. The relative predominance of antigenic modulation and complement activation that represent competing sequelae of IgG binding to the surface AQP4 may determine an individual’s clinical presentation, response to therapy, and disease course. The rapid endocytosis and degradation of surface AQP4 initiated by IgG binding coupled with the rapid replenishment of newly synthesized AQP4 also supports a potentially reversible insult, at least during early disease stages.
A recent study further demonstrated that exposure to NMO patient serum and active complement compromised the membrane integrity of CNS-derived astrocytes. Without complement, astrocyte membranes remained intact, but AQP4 was endocytosed with concomitant loss of sodium-dependent glutamate transport and loss of the excitatory transporter, EAAT2. These findings suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Furthermore, Dr. Lucchinetti reported that NMO lesions demonstrated marked reduction in EAAT2 in regions of AQP4 loss. In summary, binding of NMO-IgG to astrocytic AQP4 initiates not only complement activation, but AQP4 and EAAT2 downregulation, which would be expected to disrupt glutamate homeostasis. This could lead to injury of oligodendrocytes that express calcium-permeable glutamate receptors.
Dr. Lucchinetti discussed several possible mechanisms that might initiate demyelination in NMO. First, oligodendrocyte are more susceptible than astrocytes to lethal injury by noxious stimuli, and would be expected to be injured at the paranode where they directly contact AQP4 containing astrocytic foot processes. Second, demyelination could be secondary as a result of axonal injury due to alterations in the ionic microenvironment at the internode. Third, glutamate toxicity may contribute to demyelination.
“NMO IgG can produce three potentially pathogenic outcomes—AQP4 and EAAT2 modulation, complement activation, and reduced glutamate uptake,” she said. “Treatment strategies targeting complement activation and glutamate excitotoxicity may prove effective."

Suggested Reading
Hinson SR, Roemer SF, Lucchinetti CF, et al. Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J Exp Med. 2008;205(11):2473-2481.
Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal MS binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473-477.
Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.
McKeon A, Fryer JP, Apiwattanakul M, et al. Diagnosis of neuromyelitis spectrum disorders: comparative sensitivities and specificities of immunohistochemical and immunoprecipitation assays. Arch Neurol. 2009;66(9):1134-1138.
Pittock SJ, Lennon VA, Krecke K, et al. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006;63(3):390-396.
Pittock SJ, Weinshenker BG, Lucchinetti CF, et al. Neuromyelitis optica brain lesions localized to sites of high aquaporin 4 expression. Arch Neurol. 2006;63(7):964-968.
Roemer SF, Parisi JE, Lennon VA, et al. Pattern specific loss of aquaporin 4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain. 2007;130(Pt 5):1194-1205.
Wingerchuk Dean M, Lennon V, et al. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):805-815.

Paroxysmal Dystonia Is Associated With Neuromyelitis Optica

SAN FRANCISCO—Paroxysmal dystonia occurs in 14% of patients with neuromyelitis optica, according to research presented at the 135th Annual Meeting of the American Neurological Association. The rate is similar to its association with multiple sclerosis (MS) and may be a presenting sign in both neuromyelitis optica and MS, reported Nida Usmani, MD, and colleagues.

“The pathogenesis of paroxysmal dystonia in neuromyelitis optica is unknown,” stated Dr. Usmani, of the Department of Neurology at the University of Miami. “In MS, it has been hypothesized to be due to ephaptic transmission in demyelinated axons.”

The researchers conducted a retrospective, longitudinal study of 57 patients with neuromyelitis optica. Eight patients had paroxysmal dystonia, which was defined as spontaneous brief, frequent, stereotyped episodes of abnormal posturing of an extremity, face, or neck. The mean age of onset was 37.4 (range, 13.8 to 54.2), with a seven-to-one ratio of females to males. Neuromyelitis optica antibody was found in one of five patients.

Paroxysmal dystonia appeared after a mean of 24.6 months of diagnosis of neuromyelitis optica. In two patients, paroxysmal dystonia was their initial presentation, and the average interval between onset of paroxysmal dystonia and development of other neurologic deficit was 2.5 months. Five patients had single limbs affected, two patients had ipsilateral arm and leg involvement, and one patient had tonic spasms. Two patients had cervical spine lesions on MRI. Seven patients responded to carbamazepine within one week.

“The incidence of paroxysmal dystonia in our neuromyelitis optica case series was 14%, which is similar to reports of its association with MS—3.8% to 17%,” stated Dr. Usmani. “Heretofore, only one well characterized case of neuromyelitis optica with paroxysmal dystonia has been reported. Unfamiliarity with this association can lead to a diagnostic dilemma, especially in cases of paroxysmal dystonia as a presenting symptom.”

Findings support a pathogenic role for an autoantibody of AQP4 specificity in neuromyelitis optica.

SAN FRANCISCO—A complement activating aquaporin-4 (AQP4)-specific autoantibody has a pathogenic role in initiating neuromyelitis optica (NMO) lesions and distinguishes NMO from multiple sclerosis (MS), according to research presented at the 135th Annual Meeting of the American Neurological Association.
Clinical presentation of NMO differs from MS in a number of ways, explained Claudia Lucchinetti, MD, of the Mayo Clinic Rochester in Minnesota, and member of the Mayo Clinic NMO Consortium. NMO onset tends to occur at an older age, affects more females than males, and is more common in non-Caucasians. NMO is typically a relapsing disease, and unlike MS, a progressive course is distinctly unusual. In contrast to MS, brain MRI scans are often normal early in the disease, while spinal cord MRIs typically show long lesions spanning three or more intervertebral segments, which are not typically seen in adult MS. Oligoclonal bands in the spinal fluid are rare in NMO, whereas pleocytosis is common. NMO can be associated with other autoimmune disorders, including myasthenia gravis. Patients with active NMO respond favorably to antibody-depleting therapies.
In 2002, Dr. Lucchinetti and colleagues described the presence of deposits of immunoglobulin G (IgG) and immunoglobulin M (IgM) co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels in active NMO lesions, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. In 2004, Vanda Lennon, MD, PhD, and colleagues at the Mayo Clinic reported a specific serum autoantibody marker that was 73% sensitive and more than 90% specific for clinically defined NMO. Its selective binding to the abluminal face of microvessels, pia, subpia and Virchow-Robin sheaths was reminiscent of the localization of immune complexes in NMO patients’ spinal cord tissues described by Lucchinetti and colleagues.
“With the discovery of the biomarker, a spectrum of neurologic disorders has been identified associated with the presence of NMO-IgG, including not only NMO, but also isolated or recurrent longitudinally extensive transverse myelitis, or optic neuritis, encephalopathy, intractable nausea and vomiting, a posterior reversible leukoencephalopathy (PRES)-like syndrome, endocrinopathies, and even narcolepsy,” she said.
Aquaporin-4
Subsequent studies led by Dr. Lennon identified AQP4 as the target auto-antigen in NMO. AQP4 is the dominant CNS water channel, which regulates bidirectional water flux between the blood and brain, and the brain and spinal fluid, and is concentrated at the astrocytic end-feet. It is expressed in two isoforms, M1 and M23, and consists of six membranes that determine the channel’s selectivity for water molecules, Dr. Lucchinetti said.
AQP4 is found on the surfaces of astrocytes, concentrated in periventricular regions, circumventricular organs, and spinal cord gray matter in healthy controls. Normal AQP4 expression parallels the classic ring and rosette staining pattern of immune complex deposition observed in active NMO lesions. In contrast to active MS lesions, which show an increase in AQP4 immunoreactivity, NMO lesions show a striking loss of AQP4, she explained. “Interestingly, myelin may be relatively preserved in some of these lesions, despite the profound loss of AQP4,” said Dr. Lucchinetti.
Brain Lesions in NMO
MRI detects brain lesions in 60% of NMO patients, which include NMO-specific brain lesions in regions of high AQP4 expression (eg, area postrema, hypothalamus), as well as supratentorial lesions that are either nonspecific or MS-like in appearance. The presence of these supratentorial brain lesions has suggested a possible pathologic overlap of NMO and MS. However, comparison of supratentorial (ST) NMO lesions with opticospinal (OS) NMO lesions, as well as supratentorial MS lesions, confirmed that the pathology of NMO ST lesions is similar to NMO OS lesions with respect to type of inflammation, presence of perivascular immune complex deposits and AQP4 loss. Dr. Lucchinetti suggests these findings indicate that NMO ST and OS lesions have a shared pathogenesis.
Clinical reports have also described intractable hiccups, nausea, and vomiting in NMO. NMO specific medullary lesions have been observed in the area postrema, which are characterized by a selective and targeted loss of AQP4, and likely reflect the pathologic substrate of intractable nausea and vomiting reported in some NMO patients. A study in press by members of the Mayo Clinic NMO consortium suggests that the area postrema may even be the first point of attack in NMO in at least 12% of NMO cases, Dr. Lucchinetti reported.
The Role of NMO IgG
In vitro studies demonstrate that NMO-IgG binds selectively to the surface of living target cell membranes expressing AQP4, a prerequisite for IgG to affect organ-specific pathogenicity. This binding initiates two potentially competing outcomes: 1) rapid downregulation of AQP4 via endocytosis/degradation; and 2) activation of the lytic complement cascade. The relative predominance of antigenic modulation and complement activation that represent competing sequelae of IgG binding to the surface AQP4 may determine an individual’s clinical presentation, response to therapy, and disease course. The rapid endocytosis and degradation of surface AQP4 initiated by IgG binding coupled with the rapid replenishment of newly synthesized AQP4 also supports a potentially reversible insult, at least during early disease stages.
A recent study further demonstrated that exposure to NMO patient serum and active complement compromised the membrane integrity of CNS-derived astrocytes. Without complement, astrocyte membranes remained intact, but AQP4 was endocytosed with concomitant loss of sodium-dependent glutamate transport and loss of the excitatory transporter, EAAT2. These findings suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Furthermore, Dr. Lucchinetti reported that NMO lesions demonstrated marked reduction in EAAT2 in regions of AQP4 loss. In summary, binding of NMO-IgG to astrocytic AQP4 initiates not only complement activation, but AQP4 and EAAT2 downregulation, which would be expected to disrupt glutamate homeostasis. This could lead to injury of oligodendrocytes that express calcium-permeable glutamate receptors.
Dr. Lucchinetti discussed several possible mechanisms that might initiate demyelination in NMO. First, oligodendrocyte are more susceptible than astrocytes to lethal injury by noxious stimuli, and would be expected to be injured at the paranode where they directly contact AQP4 containing astrocytic foot processes. Second, demyelination could be secondary as a result of axonal injury due to alterations in the ionic microenvironment at the internode. Third, glutamate toxicity may contribute to demyelination.
“NMO IgG can produce three potentially pathogenic outcomes—AQP4 and EAAT2 modulation, complement activation, and reduced glutamate uptake,” she said. “Treatment strategies targeting complement activation and glutamate excitotoxicity may prove effective."

Suggested Reading
Hinson SR, Roemer SF, Lucchinetti CF, et al. Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J Exp Med. 2008;205(11):2473-2481.
Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal MS binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473-477.
Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.
McKeon A, Fryer JP, Apiwattanakul M, et al. Diagnosis of neuromyelitis spectrum disorders: comparative sensitivities and specificities of immunohistochemical and immunoprecipitation assays. Arch Neurol. 2009;66(9):1134-1138.
Pittock SJ, Lennon VA, Krecke K, et al. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006;63(3):390-396.
Pittock SJ, Weinshenker BG, Lucchinetti CF, et al. Neuromyelitis optica brain lesions localized to sites of high aquaporin 4 expression. Arch Neurol. 2006;63(7):964-968.
Roemer SF, Parisi JE, Lennon VA, et al. Pattern specific loss of aquaporin 4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain. 2007;130(Pt 5):1194-1205.
Wingerchuk Dean M, Lennon V, et al. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):805-815.

Paroxysmal Dystonia Is Associated With Neuromyelitis Optica

SAN FRANCISCO—Paroxysmal dystonia occurs in 14% of patients with neuromyelitis optica, according to research presented at the 135th Annual Meeting of the American Neurological Association. The rate is similar to its association with multiple sclerosis (MS) and may be a presenting sign in both neuromyelitis optica and MS, reported Nida Usmani, MD, and colleagues.

“The pathogenesis of paroxysmal dystonia in neuromyelitis optica is unknown,” stated Dr. Usmani, of the Department of Neurology at the University of Miami. “In MS, it has been hypothesized to be due to ephaptic transmission in demyelinated axons.”

The researchers conducted a retrospective, longitudinal study of 57 patients with neuromyelitis optica. Eight patients had paroxysmal dystonia, which was defined as spontaneous brief, frequent, stereotyped episodes of abnormal posturing of an extremity, face, or neck. The mean age of onset was 37.4 (range, 13.8 to 54.2), with a seven-to-one ratio of females to males. Neuromyelitis optica antibody was found in one of five patients.

Paroxysmal dystonia appeared after a mean of 24.6 months of diagnosis of neuromyelitis optica. In two patients, paroxysmal dystonia was their initial presentation, and the average interval between onset of paroxysmal dystonia and development of other neurologic deficit was 2.5 months. Five patients had single limbs affected, two patients had ipsilateral arm and leg involvement, and one patient had tonic spasms. Two patients had cervical spine lesions on MRI. Seven patients responded to carbamazepine within one week.

“The incidence of paroxysmal dystonia in our neuromyelitis optica case series was 14%, which is similar to reports of its association with MS—3.8% to 17%,” stated Dr. Usmani. “Heretofore, only one well characterized case of neuromyelitis optica with paroxysmal dystonia has been reported. Unfamiliarity with this association can lead to a diagnostic dilemma, especially in cases of paroxysmal dystonia as a presenting symptom.”

Findings support a pathogenic role for an autoantibody of AQP4 specificity in neuromyelitis optica.

SAN FRANCISCO—A complement activating aquaporin-4 (AQP4)-specific autoantibody has a pathogenic role in initiating neuromyelitis optica (NMO) lesions and distinguishes NMO from multiple sclerosis (MS), according to research presented at the 135th Annual Meeting of the American Neurological Association.
Clinical presentation of NMO differs from MS in a number of ways, explained Claudia Lucchinetti, MD, of the Mayo Clinic Rochester in Minnesota, and member of the Mayo Clinic NMO Consortium. NMO onset tends to occur at an older age, affects more females than males, and is more common in non-Caucasians. NMO is typically a relapsing disease, and unlike MS, a progressive course is distinctly unusual. In contrast to MS, brain MRI scans are often normal early in the disease, while spinal cord MRIs typically show long lesions spanning three or more intervertebral segments, which are not typically seen in adult MS. Oligoclonal bands in the spinal fluid are rare in NMO, whereas pleocytosis is common. NMO can be associated with other autoimmune disorders, including myasthenia gravis. Patients with active NMO respond favorably to antibody-depleting therapies.
In 2002, Dr. Lucchinetti and colleagues described the presence of deposits of immunoglobulin G (IgG) and immunoglobulin M (IgM) co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels in active NMO lesions, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. In 2004, Vanda Lennon, MD, PhD, and colleagues at the Mayo Clinic reported a specific serum autoantibody marker that was 73% sensitive and more than 90% specific for clinically defined NMO. Its selective binding to the abluminal face of microvessels, pia, subpia and Virchow-Robin sheaths was reminiscent of the localization of immune complexes in NMO patients’ spinal cord tissues described by Lucchinetti and colleagues.
“With the discovery of the biomarker, a spectrum of neurologic disorders has been identified associated with the presence of NMO-IgG, including not only NMO, but also isolated or recurrent longitudinally extensive transverse myelitis, or optic neuritis, encephalopathy, intractable nausea and vomiting, a posterior reversible leukoencephalopathy (PRES)-like syndrome, endocrinopathies, and even narcolepsy,” she said.
Aquaporin-4
Subsequent studies led by Dr. Lennon identified AQP4 as the target auto-antigen in NMO. AQP4 is the dominant CNS water channel, which regulates bidirectional water flux between the blood and brain, and the brain and spinal fluid, and is concentrated at the astrocytic end-feet. It is expressed in two isoforms, M1 and M23, and consists of six membranes that determine the channel’s selectivity for water molecules, Dr. Lucchinetti said.
AQP4 is found on the surfaces of astrocytes, concentrated in periventricular regions, circumventricular organs, and spinal cord gray matter in healthy controls. Normal AQP4 expression parallels the classic ring and rosette staining pattern of immune complex deposition observed in active NMO lesions. In contrast to active MS lesions, which show an increase in AQP4 immunoreactivity, NMO lesions show a striking loss of AQP4, she explained. “Interestingly, myelin may be relatively preserved in some of these lesions, despite the profound loss of AQP4,” said Dr. Lucchinetti.
Brain Lesions in NMO
MRI detects brain lesions in 60% of NMO patients, which include NMO-specific brain lesions in regions of high AQP4 expression (eg, area postrema, hypothalamus), as well as supratentorial lesions that are either nonspecific or MS-like in appearance. The presence of these supratentorial brain lesions has suggested a possible pathologic overlap of NMO and MS. However, comparison of supratentorial (ST) NMO lesions with opticospinal (OS) NMO lesions, as well as supratentorial MS lesions, confirmed that the pathology of NMO ST lesions is similar to NMO OS lesions with respect to type of inflammation, presence of perivascular immune complex deposits and AQP4 loss. Dr. Lucchinetti suggests these findings indicate that NMO ST and OS lesions have a shared pathogenesis.
Clinical reports have also described intractable hiccups, nausea, and vomiting in NMO. NMO specific medullary lesions have been observed in the area postrema, which are characterized by a selective and targeted loss of AQP4, and likely reflect the pathologic substrate of intractable nausea and vomiting reported in some NMO patients. A study in press by members of the Mayo Clinic NMO consortium suggests that the area postrema may even be the first point of attack in NMO in at least 12% of NMO cases, Dr. Lucchinetti reported.
The Role of NMO IgG
In vitro studies demonstrate that NMO-IgG binds selectively to the surface of living target cell membranes expressing AQP4, a prerequisite for IgG to affect organ-specific pathogenicity. This binding initiates two potentially competing outcomes: 1) rapid downregulation of AQP4 via endocytosis/degradation; and 2) activation of the lytic complement cascade. The relative predominance of antigenic modulation and complement activation that represent competing sequelae of IgG binding to the surface AQP4 may determine an individual’s clinical presentation, response to therapy, and disease course. The rapid endocytosis and degradation of surface AQP4 initiated by IgG binding coupled with the rapid replenishment of newly synthesized AQP4 also supports a potentially reversible insult, at least during early disease stages.
A recent study further demonstrated that exposure to NMO patient serum and active complement compromised the membrane integrity of CNS-derived astrocytes. Without complement, astrocyte membranes remained intact, but AQP4 was endocytosed with concomitant loss of sodium-dependent glutamate transport and loss of the excitatory transporter, EAAT2. These findings suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Furthermore, Dr. Lucchinetti reported that NMO lesions demonstrated marked reduction in EAAT2 in regions of AQP4 loss. In summary, binding of NMO-IgG to astrocytic AQP4 initiates not only complement activation, but AQP4 and EAAT2 downregulation, which would be expected to disrupt glutamate homeostasis. This could lead to injury of oligodendrocytes that express calcium-permeable glutamate receptors.
Dr. Lucchinetti discussed several possible mechanisms that might initiate demyelination in NMO. First, oligodendrocyte are more susceptible than astrocytes to lethal injury by noxious stimuli, and would be expected to be injured at the paranode where they directly contact AQP4 containing astrocytic foot processes. Second, demyelination could be secondary as a result of axonal injury due to alterations in the ionic microenvironment at the internode. Third, glutamate toxicity may contribute to demyelination.
“NMO IgG can produce three potentially pathogenic outcomes—AQP4 and EAAT2 modulation, complement activation, and reduced glutamate uptake,” she said. “Treatment strategies targeting complement activation and glutamate excitotoxicity may prove effective."

Suggested Reading
Hinson SR, Roemer SF, Lucchinetti CF, et al. Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J Exp Med. 2008;205(11):2473-2481.
Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal MS binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473-477.
Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112.
McKeon A, Fryer JP, Apiwattanakul M, et al. Diagnosis of neuromyelitis spectrum disorders: comparative sensitivities and specificities of immunohistochemical and immunoprecipitation assays. Arch Neurol. 2009;66(9):1134-1138.
Pittock SJ, Lennon VA, Krecke K, et al. Brain abnormalities in neuromyelitis optica. Arch Neurol. 2006;63(3):390-396.
Pittock SJ, Weinshenker BG, Lucchinetti CF, et al. Neuromyelitis optica brain lesions localized to sites of high aquaporin 4 expression. Arch Neurol. 2006;63(7):964-968.
Roemer SF, Parisi JE, Lennon VA, et al. Pattern specific loss of aquaporin 4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain. 2007;130(Pt 5):1194-1205.
Wingerchuk Dean M, Lennon V, et al. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):805-815.

Paroxysmal Dystonia Is Associated With Neuromyelitis Optica

SAN FRANCISCO—Paroxysmal dystonia occurs in 14% of patients with neuromyelitis optica, according to research presented at the 135th Annual Meeting of the American Neurological Association. The rate is similar to its association with multiple sclerosis (MS) and may be a presenting sign in both neuromyelitis optica and MS, reported Nida Usmani, MD, and colleagues.

“The pathogenesis of paroxysmal dystonia in neuromyelitis optica is unknown,” stated Dr. Usmani, of the Department of Neurology at the University of Miami. “In MS, it has been hypothesized to be due to ephaptic transmission in demyelinated axons.”

The researchers conducted a retrospective, longitudinal study of 57 patients with neuromyelitis optica. Eight patients had paroxysmal dystonia, which was defined as spontaneous brief, frequent, stereotyped episodes of abnormal posturing of an extremity, face, or neck. The mean age of onset was 37.4 (range, 13.8 to 54.2), with a seven-to-one ratio of females to males. Neuromyelitis optica antibody was found in one of five patients.

Paroxysmal dystonia appeared after a mean of 24.6 months of diagnosis of neuromyelitis optica. In two patients, paroxysmal dystonia was their initial presentation, and the average interval between onset of paroxysmal dystonia and development of other neurologic deficit was 2.5 months. Five patients had single limbs affected, two patients had ipsilateral arm and leg involvement, and one patient had tonic spasms. Two patients had cervical spine lesions on MRI. Seven patients responded to carbamazepine within one week.

“The incidence of paroxysmal dystonia in our neuromyelitis optica case series was 14%, which is similar to reports of its association with MS—3.8% to 17%,” stated Dr. Usmani. “Heretofore, only one well characterized case of neuromyelitis optica with paroxysmal dystonia has been reported. Unfamiliarity with this association can lead to a diagnostic dilemma, especially in cases of paroxysmal dystonia as a presenting symptom.”

Onabotulinum toxin A may have a role in treating lower extremity spasticity and aiding walking in patients with MS, researchers report.

SAN ANTONIO—Onabotulinum toxin A (Botox) may help improve ambulation in patients with multiple sclerosis (MS), according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“We observed improvements in ambulation speed, endurance, ambulation on uneven surfaces, and in the ability to ascend and descend inclines and stairs,” reported Christine Short, MD. “Overall improvements in total ambulation capability occurred. Subjectively, individuals also reported improved clonus, decreased tone, decreased pain, decreased muscle spasm, and greater ease of ambulation.” Dr. Short is an Assistant Professor, Division of Physical Medicine, Rehabilitation, and Neurosurgery, Dalhousie University in Halifax, Nova Scotia, Canada.

The findings are based on a case series of five patients with MS whose walking abilities had been compromised by spasticity in the lower extremities. Each participant had problems with extensor and inversion spasticity in one or both lower extremities at the time of treatment. The patients also complained of catching their toes during ambulation, which led to tripping and falling, painful muscle spasms, clonus, and spasticity that interfered with sleep.

All patients participated in physical therapy and were treated with oral antispasticity agents. “In each case, focal neurolysis with Botox was considered when, clinically, there was a suboptimal response to oral and physical therapies or if the therapies were not tolerated due to side effects,” Dr. Short noted.

The total dosage of Botox for each patient ranged from 200 units to 400 units. The investigators measured ambulation speed and endurance before Botox therapy and six weeks after the therapy, “when Botox would be having a maximal effect,” Dr. Short stated. Speed and endurance were determined with use of the six-minute walk test.

“All the individuals treated showed improvements in ambulation speed,” reported Dr. Short. “All subjects also showed improvements in ambulation endurance. Some of the improvements were greater than twofold above baseline. Subjectively, individuals also described improvements in other areas, including decreased pain and decreased clonus, decreased muscle spasms, and greater ease of ambulation in all five cases. Clinically, we observed decreased spasticity in the treated muscles and improved gait."

Dr. Short pointed out that the small sample size of patients did not allow for a more rigorous statistical analysis. “However,” she concluded, “our very interesting observations suggest that further research would be valuable to assess the usefulness of Botox as a treatment for improving ambulation in persons with MS and lower extremity spasticity.

—Rebecca K. Abma

Onabotulinum toxin A may have a role in treating lower extremity spasticity and aiding walking in patients with MS, researchers report.

SAN ANTONIO—Onabotulinum toxin A (Botox) may help improve ambulation in patients with multiple sclerosis (MS), according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“We observed improvements in ambulation speed, endurance, ambulation on uneven surfaces, and in the ability to ascend and descend inclines and stairs,” reported Christine Short, MD. “Overall improvements in total ambulation capability occurred. Subjectively, individuals also reported improved clonus, decreased tone, decreased pain, decreased muscle spasm, and greater ease of ambulation.” Dr. Short is an Assistant Professor, Division of Physical Medicine, Rehabilitation, and Neurosurgery, Dalhousie University in Halifax, Nova Scotia, Canada.

The findings are based on a case series of five patients with MS whose walking abilities had been compromised by spasticity in the lower extremities. Each participant had problems with extensor and inversion spasticity in one or both lower extremities at the time of treatment. The patients also complained of catching their toes during ambulation, which led to tripping and falling, painful muscle spasms, clonus, and spasticity that interfered with sleep.

All patients participated in physical therapy and were treated with oral antispasticity agents. “In each case, focal neurolysis with Botox was considered when, clinically, there was a suboptimal response to oral and physical therapies or if the therapies were not tolerated due to side effects,” Dr. Short noted.

The total dosage of Botox for each patient ranged from 200 units to 400 units. The investigators measured ambulation speed and endurance before Botox therapy and six weeks after the therapy, “when Botox would be having a maximal effect,” Dr. Short stated. Speed and endurance were determined with use of the six-minute walk test.

“All the individuals treated showed improvements in ambulation speed,” reported Dr. Short. “All subjects also showed improvements in ambulation endurance. Some of the improvements were greater than twofold above baseline. Subjectively, individuals also described improvements in other areas, including decreased pain and decreased clonus, decreased muscle spasms, and greater ease of ambulation in all five cases. Clinically, we observed decreased spasticity in the treated muscles and improved gait."

Dr. Short pointed out that the small sample size of patients did not allow for a more rigorous statistical analysis. “However,” she concluded, “our very interesting observations suggest that further research would be valuable to assess the usefulness of Botox as a treatment for improving ambulation in persons with MS and lower extremity spasticity.

—Rebecca K. Abma

Onabotulinum toxin A may have a role in treating lower extremity spasticity and aiding walking in patients with MS, researchers report.

SAN ANTONIO—Onabotulinum toxin A (Botox) may help improve ambulation in patients with multiple sclerosis (MS), according to research presented at the 24th Annual Meeting of the Consortium of Multiple Sclerosis Centers.

“We observed improvements in ambulation speed, endurance, ambulation on uneven surfaces, and in the ability to ascend and descend inclines and stairs,” reported Christine Short, MD. “Overall improvements in total ambulation capability occurred. Subjectively, individuals also reported improved clonus, decreased tone, decreased pain, decreased muscle spasm, and greater ease of ambulation.” Dr. Short is an Assistant Professor, Division of Physical Medicine, Rehabilitation, and Neurosurgery, Dalhousie University in Halifax, Nova Scotia, Canada.

The findings are based on a case series of five patients with MS whose walking abilities had been compromised by spasticity in the lower extremities. Each participant had problems with extensor and inversion spasticity in one or both lower extremities at the time of treatment. The patients also complained of catching their toes during ambulation, which led to tripping and falling, painful muscle spasms, clonus, and spasticity that interfered with sleep.

All patients participated in physical therapy and were treated with oral antispasticity agents. “In each case, focal neurolysis with Botox was considered when, clinically, there was a suboptimal response to oral and physical therapies or if the therapies were not tolerated due to side effects,” Dr. Short noted.

The total dosage of Botox for each patient ranged from 200 units to 400 units. The investigators measured ambulation speed and endurance before Botox therapy and six weeks after the therapy, “when Botox would be having a maximal effect,” Dr. Short stated. Speed and endurance were determined with use of the six-minute walk test.

“All the individuals treated showed improvements in ambulation speed,” reported Dr. Short. “All subjects also showed improvements in ambulation endurance. Some of the improvements were greater than twofold above baseline. Subjectively, individuals also described improvements in other areas, including decreased pain and decreased clonus, decreased muscle spasms, and greater ease of ambulation in all five cases. Clinically, we observed decreased spasticity in the treated muscles and improved gait."

Dr. Short pointed out that the small sample size of patients did not allow for a more rigorous statistical analysis. “However,” she concluded, “our very interesting observations suggest that further research would be valuable to assess the usefulness of Botox as a treatment for improving ambulation in persons with MS and lower extremity spasticity.

—Rebecca K. Abma

Hyperinsulinemia and hyperglycemia due to insulin resistance may accelerate the formation of neuritic plaques in combination with the effects of apolipoprotein (APOE) e4, as reported in the August 25 online Neurology. This is the conclusion from autopsy studies of 135 residents of Hisayama, Japan, who died between 1998 and 2003. In 1988, the subjects underwent a 75-g oral glucose tolerance test in which measurements of diabetes-related factors, including fasting glucose, two-hour postload plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were taken. The investigators found that higher levels of postload glucose, fasting insulin, and HOMA-IR were associated with an increased risk for neuritic plaques. In addition, “the coexistence of hyperglycemia and APOE e4 increased the risk for neuritic plaque formation,” the researchers reported. “A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.”

A novel gamma-secretase activating protein (GSAP) that “drastically and selectively increases beta-amyloid production” without impairing Notch cleavage was reported in the September 1 online Nature. According to the paper, GSAP stimulates beta-amyloid production in vitro, while mouse models have shown that reducing GSAP decreases beta-amyloid concentrations. The researchers demonstrated that the anti-cancer drug imatinib prevents GSAP interaction with the gamma-secretase substrate amyloid precursor protein carboxy-terminal fragment, without affecting Notch cleavage, and thereby may provide a new therapeutic target for the treatment and prevention of Alzheimer’s disease.
Brain games aimed at stimulating mental acuity appear to slow cognitive decline prior to the onset of dementia, but accelerate it afterward, according to a study in the September 1 online Neurology. Researchers assessed cognitive performance of older subjects at three-year intervals as a composite measure of global cognition, while a subset was sampled for clinical evaluation. Subjects were dementia-free at baseline, at which point they rated the frequency at which they engaged in cognitively stimulating activity. “During follow-up, the annual rate of global cognitive decline in persons without cognitive impairment was reduced by 52% for each additional point on the cognitive activity scale,” the investigators reported. “In the mild cognitive impairment group, cognitive decline rate was unrelated to cognitive activity. In Alzheimer’s disease, the mean rate of decline per year increased by 42% for each point on the cognitive activity scale.”
Researchers have found a new genetic risk factor for amyotrophic lateral sclerosis (ALS), as reported in the August 26 Nature. The study authors showed that ataxin 2 (ATXN2) is a potent modifier of TDP-43 toxicity in animal and cellular models and analyzed the length of the polyQ repeat in the ATXN2 gene in 915 patients with ALS. “We found that intermediate-length polyQ expansions (27 to 33 glutamines) in ATXN2 were significantly associated with ALS,” the investigators stated. “These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43 ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.”
Two studies in the August 27 online Lancet Neurology have identified genetic variations on chromosome 9 as having a role in the development of amyotrophic lateral sclerosis (ALS). In one study of 442 Finnish patients with ALS, researchers found data suggesting the presence of a founder mutation for chromosome 9p21-linked ALS. “The overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.” A second study of 599 patients with ALS from the UK found “strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent genome-wide association studies of ALS and linkage studies of ALS-frontotemporal dementia.”
Infants born at 37 or 38 weeks gestation or at 42 weeks or later have an increased risk for cerebral palsy, compared with those born at 40 weeks, researchers reported in the September 1 JAMA. Among 1,938 children with cerebral palsy, infants born at 40 weeks had the lowest risk of the disease, with a prevalence of 0.99/1,000. At 37 weeks, the prevalence was 1.91 (relative risk [RR], 1.9), at 38 weeks the prevalence was 1.25 (RR, 1.3), at 42 weeks the prevalence was 1.36 (RR, 1.4), and after 42 weeks the prevalence was 1.44 (RR, 1.4). “These associations were even stronger in a subset with gestational age based on ultrasound measurements: at 37 weeks the prevalence was 1.17/1,000 and the RR was 3.7,” the investigators reported. “At 42 weeks the prevalence was 0.85/1,000 and the RR was 2.4.”
Use of anticholinergic medications may increase the risk of cognitive impairment, according to a study in the July 13 Neurology. In a six-year longitudinal, observational study of 1,652 community-dwelling African American subjects older than 70, investigators found the number of definite anticholinergics used was associated with a 1.46-fold increased risk of cognitive impairment. Possible anticholinergics were not associated with an increased risk of cognitive impairment. Medications were rated as possible or definite based on the Anticholinergic Cognitive Burden scale. In addition, the investigators found that the increased risk of cognitive impairment was evident among definite anticholinergic users regardless of their apolipoprotein (APOE) e4 allele status. “Limiting the clinical use of definite anticholinergics may reduce the incidence of cognitive impairment among African Americans,” the study authors wrote.
Veterans who experienced post-traumatic stress disorder (PTSD) have a higher incidence and prevalence of dementia, researchers reported in the September Journal of the American Geriatrics Society. In an administrative database study of veterans enrolled in the South Central VA Healthcare Network, which comprises Arkansas, Louisiana, Mississippi, Oklahoma, and parts of Alabama, Florida, Missouri, and Texas, the investigators identified subjects 65 and older who had a diagnosis of PTSD or received a Purple Heart to compare with a group of contemporaries without PTSD or a Purple Heart. After controlling for confounding factors in a multivariate logistic regression, those with PTSD who had not received a Purple Heart had the highest rates of dementia. “It is unclear whether this is due to a common risk factor underlying PTSD and dementia or to PTSD being a risk factor for dementia,” the investigators wrote. “Regardless, this study suggests that veterans with PTSD should be screened more closely for dementia. Because PTSD is so common in veterans, this association has important implications for veteran care.”
The FDA has approved Silenor (doxepin) for the treatment of insomnia characterized by difficulty with sleep maintenance. The first and only prescription sleep medicine approved for treating patients who have episodes of frequent waking during the night or waking too early and being unable to return to sleep, the oral tablet formulation is now commercially available by prescription in 3-mg and 6-mg doses. According to a representative for Somaxon Pharmaceuticals, Inc, in San Diego, “clinical studies demonstrate that Silenor supports seven to eight hours of sleep with no next-day residual effects in most patients and no evidence of abuse potential or physical dependence.”
Subclinical multiple sclerosis (MS) activity may have a strong seasonal pattern, peaking during the spring and summer months, according to a study published in the August 31 issue of Neurology. Basing their findings on noncontrast brain MRI, researchers reported that “the observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.” New T2 activity showed a likelihood of occurring two to three times higher from March to August than during the rest of the year, which “correlated strongly with regional climate data, in particular solar radiation,” the investigators wrote. In addition, disease intensity was elevated during the summer season. “The elevated risk season appears to lessen for progressive MS and occur about two months earlier,” the authors wrote.
An association between Parkinson’s disease and a gene in the human leukocyte antigen (HLA) region was found in a genome-wide association study (GWAS), researchers reported in the September issue of Nature Genetics. The finding links the involvement of the immune system in Parkinson’s disease and offers new targets for drug development, the investigators stated. The GWAS of 2,000 subjects and 1,986 controls, all of whom were Americans of European ancestry, found an association peak at rs3129882. The findings lend “strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson’s disease pathogenesis,” the researchers wrote. The study also confirmed associations with SNCA2,6-8 and MAPT3,7-9 genes, and replicated an association with GAK9.
Drinking alcohol temporarily increases the risk of acute ischemic stroke, per a study that was published in the September Stroke. In a multicenter study of 209 men and 181 women who recently had a stroke, investigators questioned subjects regarding alcohol consumption in relation to stroke onset. “We found the risk of ischemic stroke was transiently elevated for two hours after drinking as little as one serving of alcohol,” they wrote. Fourteen patients reported alcohol consumption within one hour of stroke onset, for a 2.3-fold increased risk of stroke compared to periods of nonuse. The relative risk of stroke onset was 1.6 within two hours of alcohol consumption, and by three hours, the risk returned to baseline. By 24 hours, there was a 30% lower stroke risk. “Although speculative, it is possible that the transiently increased stroke risk from moderate alcohol consumption may be outweighed by the health benefits for the next 24 hours, but consuming multiple drinks at once may result in a sharp increase in acute risk with potential increased long-term risk as well,” the researchers stated.

Hyperinsulinemia and hyperglycemia due to insulin resistance may accelerate the formation of neuritic plaques in combination with the effects of apolipoprotein (APOE) e4, as reported in the August 25 online Neurology. This is the conclusion from autopsy studies of 135 residents of Hisayama, Japan, who died between 1998 and 2003. In 1988, the subjects underwent a 75-g oral glucose tolerance test in which measurements of diabetes-related factors, including fasting glucose, two-hour postload plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were taken. The investigators found that higher levels of postload glucose, fasting insulin, and HOMA-IR were associated with an increased risk for neuritic plaques. In addition, “the coexistence of hyperglycemia and APOE e4 increased the risk for neuritic plaque formation,” the researchers reported. “A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.”

A novel gamma-secretase activating protein (GSAP) that “drastically and selectively increases beta-amyloid production” without impairing Notch cleavage was reported in the September 1 online Nature. According to the paper, GSAP stimulates beta-amyloid production in vitro, while mouse models have shown that reducing GSAP decreases beta-amyloid concentrations. The researchers demonstrated that the anti-cancer drug imatinib prevents GSAP interaction with the gamma-secretase substrate amyloid precursor protein carboxy-terminal fragment, without affecting Notch cleavage, and thereby may provide a new therapeutic target for the treatment and prevention of Alzheimer’s disease.
Brain games aimed at stimulating mental acuity appear to slow cognitive decline prior to the onset of dementia, but accelerate it afterward, according to a study in the September 1 online Neurology. Researchers assessed cognitive performance of older subjects at three-year intervals as a composite measure of global cognition, while a subset was sampled for clinical evaluation. Subjects were dementia-free at baseline, at which point they rated the frequency at which they engaged in cognitively stimulating activity. “During follow-up, the annual rate of global cognitive decline in persons without cognitive impairment was reduced by 52% for each additional point on the cognitive activity scale,” the investigators reported. “In the mild cognitive impairment group, cognitive decline rate was unrelated to cognitive activity. In Alzheimer’s disease, the mean rate of decline per year increased by 42% for each point on the cognitive activity scale.”
Researchers have found a new genetic risk factor for amyotrophic lateral sclerosis (ALS), as reported in the August 26 Nature. The study authors showed that ataxin 2 (ATXN2) is a potent modifier of TDP-43 toxicity in animal and cellular models and analyzed the length of the polyQ repeat in the ATXN2 gene in 915 patients with ALS. “We found that intermediate-length polyQ expansions (27 to 33 glutamines) in ATXN2 were significantly associated with ALS,” the investigators stated. “These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43 ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.”
Two studies in the August 27 online Lancet Neurology have identified genetic variations on chromosome 9 as having a role in the development of amyotrophic lateral sclerosis (ALS). In one study of 442 Finnish patients with ALS, researchers found data suggesting the presence of a founder mutation for chromosome 9p21-linked ALS. “The overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.” A second study of 599 patients with ALS from the UK found “strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent genome-wide association studies of ALS and linkage studies of ALS-frontotemporal dementia.”
Infants born at 37 or 38 weeks gestation or at 42 weeks or later have an increased risk for cerebral palsy, compared with those born at 40 weeks, researchers reported in the September 1 JAMA. Among 1,938 children with cerebral palsy, infants born at 40 weeks had the lowest risk of the disease, with a prevalence of 0.99/1,000. At 37 weeks, the prevalence was 1.91 (relative risk [RR], 1.9), at 38 weeks the prevalence was 1.25 (RR, 1.3), at 42 weeks the prevalence was 1.36 (RR, 1.4), and after 42 weeks the prevalence was 1.44 (RR, 1.4). “These associations were even stronger in a subset with gestational age based on ultrasound measurements: at 37 weeks the prevalence was 1.17/1,000 and the RR was 3.7,” the investigators reported. “At 42 weeks the prevalence was 0.85/1,000 and the RR was 2.4.”
Use of anticholinergic medications may increase the risk of cognitive impairment, according to a study in the July 13 Neurology. In a six-year longitudinal, observational study of 1,652 community-dwelling African American subjects older than 70, investigators found the number of definite anticholinergics used was associated with a 1.46-fold increased risk of cognitive impairment. Possible anticholinergics were not associated with an increased risk of cognitive impairment. Medications were rated as possible or definite based on the Anticholinergic Cognitive Burden scale. In addition, the investigators found that the increased risk of cognitive impairment was evident among definite anticholinergic users regardless of their apolipoprotein (APOE) e4 allele status. “Limiting the clinical use of definite anticholinergics may reduce the incidence of cognitive impairment among African Americans,” the study authors wrote.
Veterans who experienced post-traumatic stress disorder (PTSD) have a higher incidence and prevalence of dementia, researchers reported in the September Journal of the American Geriatrics Society. In an administrative database study of veterans enrolled in the South Central VA Healthcare Network, which comprises Arkansas, Louisiana, Mississippi, Oklahoma, and parts of Alabama, Florida, Missouri, and Texas, the investigators identified subjects 65 and older who had a diagnosis of PTSD or received a Purple Heart to compare with a group of contemporaries without PTSD or a Purple Heart. After controlling for confounding factors in a multivariate logistic regression, those with PTSD who had not received a Purple Heart had the highest rates of dementia. “It is unclear whether this is due to a common risk factor underlying PTSD and dementia or to PTSD being a risk factor for dementia,” the investigators wrote. “Regardless, this study suggests that veterans with PTSD should be screened more closely for dementia. Because PTSD is so common in veterans, this association has important implications for veteran care.”
The FDA has approved Silenor (doxepin) for the treatment of insomnia characterized by difficulty with sleep maintenance. The first and only prescription sleep medicine approved for treating patients who have episodes of frequent waking during the night or waking too early and being unable to return to sleep, the oral tablet formulation is now commercially available by prescription in 3-mg and 6-mg doses. According to a representative for Somaxon Pharmaceuticals, Inc, in San Diego, “clinical studies demonstrate that Silenor supports seven to eight hours of sleep with no next-day residual effects in most patients and no evidence of abuse potential or physical dependence.”
Subclinical multiple sclerosis (MS) activity may have a strong seasonal pattern, peaking during the spring and summer months, according to a study published in the August 31 issue of Neurology. Basing their findings on noncontrast brain MRI, researchers reported that “the observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.” New T2 activity showed a likelihood of occurring two to three times higher from March to August than during the rest of the year, which “correlated strongly with regional climate data, in particular solar radiation,” the investigators wrote. In addition, disease intensity was elevated during the summer season. “The elevated risk season appears to lessen for progressive MS and occur about two months earlier,” the authors wrote.
An association between Parkinson’s disease and a gene in the human leukocyte antigen (HLA) region was found in a genome-wide association study (GWAS), researchers reported in the September issue of Nature Genetics. The finding links the involvement of the immune system in Parkinson’s disease and offers new targets for drug development, the investigators stated. The GWAS of 2,000 subjects and 1,986 controls, all of whom were Americans of European ancestry, found an association peak at rs3129882. The findings lend “strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson’s disease pathogenesis,” the researchers wrote. The study also confirmed associations with SNCA2,6-8 and MAPT3,7-9 genes, and replicated an association with GAK9.
Drinking alcohol temporarily increases the risk of acute ischemic stroke, per a study that was published in the September Stroke. In a multicenter study of 209 men and 181 women who recently had a stroke, investigators questioned subjects regarding alcohol consumption in relation to stroke onset. “We found the risk of ischemic stroke was transiently elevated for two hours after drinking as little as one serving of alcohol,” they wrote. Fourteen patients reported alcohol consumption within one hour of stroke onset, for a 2.3-fold increased risk of stroke compared to periods of nonuse. The relative risk of stroke onset was 1.6 within two hours of alcohol consumption, and by three hours, the risk returned to baseline. By 24 hours, there was a 30% lower stroke risk. “Although speculative, it is possible that the transiently increased stroke risk from moderate alcohol consumption may be outweighed by the health benefits for the next 24 hours, but consuming multiple drinks at once may result in a sharp increase in acute risk with potential increased long-term risk as well,” the researchers stated.

Hyperinsulinemia and hyperglycemia due to insulin resistance may accelerate the formation of neuritic plaques in combination with the effects of apolipoprotein (APOE) e4, as reported in the August 25 online Neurology. This is the conclusion from autopsy studies of 135 residents of Hisayama, Japan, who died between 1998 and 2003. In 1988, the subjects underwent a 75-g oral glucose tolerance test in which measurements of diabetes-related factors, including fasting glucose, two-hour postload plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were taken. The investigators found that higher levels of postload glucose, fasting insulin, and HOMA-IR were associated with an increased risk for neuritic plaques. In addition, “the coexistence of hyperglycemia and APOE e4 increased the risk for neuritic plaque formation,” the researchers reported. “A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.”

A novel gamma-secretase activating protein (GSAP) that “drastically and selectively increases beta-amyloid production” without impairing Notch cleavage was reported in the September 1 online Nature. According to the paper, GSAP stimulates beta-amyloid production in vitro, while mouse models have shown that reducing GSAP decreases beta-amyloid concentrations. The researchers demonstrated that the anti-cancer drug imatinib prevents GSAP interaction with the gamma-secretase substrate amyloid precursor protein carboxy-terminal fragment, without affecting Notch cleavage, and thereby may provide a new therapeutic target for the treatment and prevention of Alzheimer’s disease.
Brain games aimed at stimulating mental acuity appear to slow cognitive decline prior to the onset of dementia, but accelerate it afterward, according to a study in the September 1 online Neurology. Researchers assessed cognitive performance of older subjects at three-year intervals as a composite measure of global cognition, while a subset was sampled for clinical evaluation. Subjects were dementia-free at baseline, at which point they rated the frequency at which they engaged in cognitively stimulating activity. “During follow-up, the annual rate of global cognitive decline in persons without cognitive impairment was reduced by 52% for each additional point on the cognitive activity scale,” the investigators reported. “In the mild cognitive impairment group, cognitive decline rate was unrelated to cognitive activity. In Alzheimer’s disease, the mean rate of decline per year increased by 42% for each point on the cognitive activity scale.”
Researchers have found a new genetic risk factor for amyotrophic lateral sclerosis (ALS), as reported in the August 26 Nature. The study authors showed that ataxin 2 (ATXN2) is a potent modifier of TDP-43 toxicity in animal and cellular models and analyzed the length of the polyQ repeat in the ATXN2 gene in 915 patients with ALS. “We found that intermediate-length polyQ expansions (27 to 33 glutamines) in ATXN2 were significantly associated with ALS,” the investigators stated. “These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43 ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.”
Two studies in the August 27 online Lancet Neurology have identified genetic variations on chromosome 9 as having a role in the development of amyotrophic lateral sclerosis (ALS). In one study of 442 Finnish patients with ALS, researchers found data suggesting the presence of a founder mutation for chromosome 9p21-linked ALS. “The overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases.” A second study of 599 patients with ALS from the UK found “strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent genome-wide association studies of ALS and linkage studies of ALS-frontotemporal dementia.”
Infants born at 37 or 38 weeks gestation or at 42 weeks or later have an increased risk for cerebral palsy, compared with those born at 40 weeks, researchers reported in the September 1 JAMA. Among 1,938 children with cerebral palsy, infants born at 40 weeks had the lowest risk of the disease, with a prevalence of 0.99/1,000. At 37 weeks, the prevalence was 1.91 (relative risk [RR], 1.9), at 38 weeks the prevalence was 1.25 (RR, 1.3), at 42 weeks the prevalence was 1.36 (RR, 1.4), and after 42 weeks the prevalence was 1.44 (RR, 1.4). “These associations were even stronger in a subset with gestational age based on ultrasound measurements: at 37 weeks the prevalence was 1.17/1,000 and the RR was 3.7,” the investigators reported. “At 42 weeks the prevalence was 0.85/1,000 and the RR was 2.4.”
Use of anticholinergic medications may increase the risk of cognitive impairment, according to a study in the July 13 Neurology. In a six-year longitudinal, observational study of 1,652 community-dwelling African American subjects older than 70, investigators found the number of definite anticholinergics used was associated with a 1.46-fold increased risk of cognitive impairment. Possible anticholinergics were not associated with an increased risk of cognitive impairment. Medications were rated as possible or definite based on the Anticholinergic Cognitive Burden scale. In addition, the investigators found that the increased risk of cognitive impairment was evident among definite anticholinergic users regardless of their apolipoprotein (APOE) e4 allele status. “Limiting the clinical use of definite anticholinergics may reduce the incidence of cognitive impairment among African Americans,” the study authors wrote.
Veterans who experienced post-traumatic stress disorder (PTSD) have a higher incidence and prevalence of dementia, researchers reported in the September Journal of the American Geriatrics Society. In an administrative database study of veterans enrolled in the South Central VA Healthcare Network, which comprises Arkansas, Louisiana, Mississippi, Oklahoma, and parts of Alabama, Florida, Missouri, and Texas, the investigators identified subjects 65 and older who had a diagnosis of PTSD or received a Purple Heart to compare with a group of contemporaries without PTSD or a Purple Heart. After controlling for confounding factors in a multivariate logistic regression, those with PTSD who had not received a Purple Heart had the highest rates of dementia. “It is unclear whether this is due to a common risk factor underlying PTSD and dementia or to PTSD being a risk factor for dementia,” the investigators wrote. “Regardless, this study suggests that veterans with PTSD should be screened more closely for dementia. Because PTSD is so common in veterans, this association has important implications for veteran care.”
The FDA has approved Silenor (doxepin) for the treatment of insomnia characterized by difficulty with sleep maintenance. The first and only prescription sleep medicine approved for treating patients who have episodes of frequent waking during the night or waking too early and being unable to return to sleep, the oral tablet formulation is now commercially available by prescription in 3-mg and 6-mg doses. According to a representative for Somaxon Pharmaceuticals, Inc, in San Diego, “clinical studies demonstrate that Silenor supports seven to eight hours of sleep with no next-day residual effects in most patients and no evidence of abuse potential or physical dependence.”
Subclinical multiple sclerosis (MS) activity may have a strong seasonal pattern, peaking during the spring and summer months, according to a study published in the August 31 issue of Neurology. Basing their findings on noncontrast brain MRI, researchers reported that “the observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity.” New T2 activity showed a likelihood of occurring two to three times higher from March to August than during the rest of the year, which “correlated strongly with regional climate data, in particular solar radiation,” the investigators wrote. In addition, disease intensity was elevated during the summer season. “The elevated risk season appears to lessen for progressive MS and occur about two months earlier,” the authors wrote.
An association between Parkinson’s disease and a gene in the human leukocyte antigen (HLA) region was found in a genome-wide association study (GWAS), researchers reported in the September issue of Nature Genetics. The finding links the involvement of the immune system in Parkinson’s disease and offers new targets for drug development, the investigators stated. The GWAS of 2,000 subjects and 1,986 controls, all of whom were Americans of European ancestry, found an association peak at rs3129882. The findings lend “strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson’s disease pathogenesis,” the researchers wrote. The study also confirmed associations with SNCA2,6-8 and MAPT3,7-9 genes, and replicated an association with GAK9.
Drinking alcohol temporarily increases the risk of acute ischemic stroke, per a study that was published in the September Stroke. In a multicenter study of 209 men and 181 women who recently had a stroke, investigators questioned subjects regarding alcohol consumption in relation to stroke onset. “We found the risk of ischemic stroke was transiently elevated for two hours after drinking as little as one serving of alcohol,” they wrote. Fourteen patients reported alcohol consumption within one hour of stroke onset, for a 2.3-fold increased risk of stroke compared to periods of nonuse. The relative risk of stroke onset was 1.6 within two hours of alcohol consumption, and by three hours, the risk returned to baseline. By 24 hours, there was a 30% lower stroke risk. “Although speculative, it is possible that the transiently increased stroke risk from moderate alcohol consumption may be outweighed by the health benefits for the next 24 hours, but consuming multiple drinks at once may result in a sharp increase in acute risk with potential increased long-term risk as well,” the researchers stated.