New and Noteworthy Information—June 2014

Older patients with migraine may be more likely to have silent brain injury than older patients without migraine, according to research published online ahead of print May 15 in Stroke. Researchers analyzed data from the Northern Manhattan Study, which quantified subclinical brain infarctions and white matter hyperintensity volumes among participants with migraine. Of the 546 participants analyzed, 41% were men, 65% were Hispanic, and mean age at MRI was 71. Patients with migraine had double the odds of subclinical brain infarction, compared with those reporting no migraine, after the investigators adjusted for sociodemographics and vascular risk factors. No association was observed between migraine with or without aura and white matter hyperintensity volume. Patients with migraine should not worry, because their risk of ischemic stroke is small, said the authors.

People who are exposed to paint, glue, or degreaser fumes at work may experience memory and thinking problems in retirement, according to a study published May 13 in Neurology. Researchers examined data for 2,143 retired utility workers who underwent cognitive testing in 2010. The authors assessed workers’ lifetime exposure to chlorinated solvents, petroleum solvents, and benzene using a job exposure matrix. Approximately 33% of participants were exposed to chlorinated solvents, 26% to benzene, and 25% to petroleum solvents. Workers highly exposed to chlorinated solvents were at risk of impairment on the Mini-Mental State Examination, the Digit Symbol Substitution Test, semantic fluency test, and the Trail Making Test B. Retirees at greatest risk for deficits had high lifetime exposure to solvents and were last exposed 12 to 30 years before testing.

Females susceptible to multiple sclerosis (MS) produce higher levels of the blood vessel receptor protein S1PR2 than males, according to data published online ahead of print May 8 in the Journal of Clinical Investigation. S1PR2 is present at high levels in the brain areas that MS typically damages. Investigators studied a mouse model of MS and found increased activity of S1PR2, which opens up the blood–brain barrier. When the researchers tested brain tissue samples obtained from 20 human patients after death, they found more S1PR2 in patients with MS than in those without the disorder. Brain tissue from females also had higher levels of S1PR2, compared with male brain tissue. These findings may help explain why more women than men get the disease, said the authors.

The FDA has required the manufacturer of the sleep drug Lunesta (eszopiclone) to lower the recommended starting dose from 2 mg to 1 mg for men and women. Data show that eszopiclone levels in some patients may be high enough on the morning after treatment to impair activities that require alertness, including driving. The 1-mg dose, taken at bedtime, can be increased to 2 mg or 3 mg if needed, but the higher doses are more likely to result in next-day impairment. Using lower doses ensures that less drug will remain in the body during the morning hours. Patients currently taking the 2-mg and 3-mg doses of Lunesta should contact their health care professional to ask for instructions, according to the FDA.

The rate of visits to an emergency department (ED) for traumatic brain injury (TBI) increased by approximately 30% between 2006 and 2010, according to research published in the May 14 issue of JAMA. The increase may be attributable to various factors, including increased awareness and diagnoses, said the authors. The investigators examined data from the Nationwide Emergency Department Sample database to determine national trends in ED visits for TBI from 2006 through 2010. An estimated 2.5 million ED visits for TBI occurred in 2010, representing a 29% increase in the rate of visits for TBI during the study period. By comparison, total ED visits increased by 3.6%. Children younger than 3 and adults older than 60 had the largest increase in TBI rates.

The pathophysiologic biomarkers and the topographic markers of Alzheimer’s disease should be revised, according to a position paper by the International Working Group published in the June issue of Lancet Neurology. The group proposed that biomarkers of Alzheimer’s pathology be restricted to those indicating the presence of tau pathology (ie, CSF or PET tau) and amyloid pathology (ie, CSF or PET amyloid). These biomarkers are specific enough to diagnose Alzheimer’s disease at any point on the disease continuum, said the authors. Downstream topographic markers of brain regional structural and metabolic changes have insufficient pathologic specificity and should not be used in diagnosis, according to the researchers. Instead, these markers can be used to measure disease progression. The group also provided diagnostic criteria for atypical, mixed, and preclinical Alzheimer’s disease.

Prenatal supplementation with docosahexaenoic acid (DHA) does not result in improved cognitive, problem-solving, or language abilities for children at age 4, according to the results of a trial published in the May 7 issue of JAMA. Investigators conducted longer-term follow-up from a previous study in which pregnant women received 800 mg/day of DHA or placebo. In the initial study, the researchers found that average cognitive, language, and motor scores did not differ between children at 18 months of age. Approximately 92% of eligible families participated in the follow-up study. The DHA group included 313 participants, and the control group included 333 participants. The investigators found that measures of cognition, the ability to perform complex mental processing, language, and executive functioning (eg, memory, reasoning, and problem solving) did not differ significantly between groups at age 4.

The FDA has informed Acorda Therapeutics that it has completed its review of the company’s new drug application for Plumiaz (diazepam) nasal spray and that the application cannot be approved in its present form. The drug was developed for the treatment of people with epilepsy who experience cluster seizures. Acorda Therapeutics is developing a response to address the items outlined in the letter. Based on the requirements for approval outlined in the letter, the company does not expect Plumiaz to receive FDA approval in 2014. Plumiaz previously received orphan drug designation for the treatment of cluster seizures. [For related news, see page 9.]

Older people with memory and thinking problems who do not have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems, according to a study published April 22 in Neurology. Researchers studied 2,627 people age 65 and older who did not have dementia at baseline. Participants underwent tests of memory and thinking skills at baseline and at three years. Follow-up lasted for an average of approximately 13 years. During the study, 1,003 participants died. About 34% of deaths occurred among patients with the fastest decline in thinking skills. Approximately 21% of participants in the group with the fastest decline in thinking skills died of cancer, compared with 29% of participants in the other two groups.

A new technique may predict with 95% accuracy which patients with stroke will benefit from IV t-PA and which will have potentially lethal bleeding in the brain, according to a study published online ahead of print May 15 in Stroke. Researchers used a computer program that shows physicians the amount of gadolinium, injected during an MRI scan, that has leaked into the brain tissue from surrounding blood vessels. By quantifying this damage in 75 patients with stroke, the researchers identified a threshold for determining how much leakage was dangerous. They applied this threshold to the records for the 75 patients to determine how well it would predict who had had a brain hemorrhage and who had not. The new test correctly predicted the outcome with 95% accuracy.

Freezing of gait in patients with Parkinson’s disease may correlate with poor quality of life, disease severity, apathy, and exposure to antimuscarinics, according to a study published online ahead of print May 19 in JAMA Neurology. Investigators performed a cross-sectional survey of 672 patients with idiopathic Parkinson’s disease. Patients with freezing of gait were identified as those with a score of 1 or greater on item 14 of the Unified Parkinson’s Disease Rating Scale (UPDRS) in the on condition. Approximately 38% of patients reported freezing of gait during the on state, which was significantly related to lower quality of life scores. Freezing of gait was also correlated with longer disease duration, higher UPDRS parts II and III scores, apathy, and a higher levodopa equivalent daily dose.

Among college football players, concussion and years of football played may have a significant inverse relationship with hippocampal volume, according to research published May 14 in JAMA. Years of football experience also may correlate with slower reaction time. Investigators conducted a cross-sectional study of 25 college football players with a history of clinician-diagnosed concussion, 25 college football players without a history of concussion, and 25 nonfootball-playing, age-, sex-, and education-matched healthy controls. Players with and without a history of concussion had smaller hippocampal volumes, compared with healthy controls. Players with a history of concussion had smaller hippocampal volumes than players without concussion. In both athlete groups, investigators found a statistically significant inverse relationship between left hippocampal volume and number of years of football played.

Deficiencies in hyaluronan can lead to spontaneous epileptic seizures, according to research published April 30 in the Journal of Neuroscience. In a multicenter study, investigators examined the role of hyaluronan using mutant mice deficient in each of the three hyaluronan synthase genes (ie, Has1, Has2, Has3). The mutant mice were prone to epileptic seizures. In Has3(-/-) mice, this phenotype likely results from a reduction in the size of the brain extracellular space (ECS), said the researchers. Among the three Has knockout models, seizures were most prevalent in Has3(-/-) mice, which also had the greatest hyaluronan reduction in the hippocampus. The results provide the first direct evidence for the physiologic role of hyaluronan in the regulation of ECS volume, according to the investigators.

—Erik Greb

Older patients with migraine may be more likely to have silent brain injury than older patients without migraine, according to research published online ahead of print May 15 in Stroke. Researchers analyzed data from the Northern Manhattan Study, which quantified subclinical brain infarctions and white matter hyperintensity volumes among participants with migraine. Of the 546 participants analyzed, 41% were men, 65% were Hispanic, and mean age at MRI was 71. Patients with migraine had double the odds of subclinical brain infarction, compared with those reporting no migraine, after the investigators adjusted for sociodemographics and vascular risk factors. No association was observed between migraine with or without aura and white matter hyperintensity volume. Patients with migraine should not worry, because their risk of ischemic stroke is small, said the authors.

People who are exposed to paint, glue, or degreaser fumes at work may experience memory and thinking problems in retirement, according to a study published May 13 in Neurology. Researchers examined data for 2,143 retired utility workers who underwent cognitive testing in 2010. The authors assessed workers’ lifetime exposure to chlorinated solvents, petroleum solvents, and benzene using a job exposure matrix. Approximately 33% of participants were exposed to chlorinated solvents, 26% to benzene, and 25% to petroleum solvents. Workers highly exposed to chlorinated solvents were at risk of impairment on the Mini-Mental State Examination, the Digit Symbol Substitution Test, semantic fluency test, and the Trail Making Test B. Retirees at greatest risk for deficits had high lifetime exposure to solvents and were last exposed 12 to 30 years before testing.

Females susceptible to multiple sclerosis (MS) produce higher levels of the blood vessel receptor protein S1PR2 than males, according to data published online ahead of print May 8 in the Journal of Clinical Investigation. S1PR2 is present at high levels in the brain areas that MS typically damages. Investigators studied a mouse model of MS and found increased activity of S1PR2, which opens up the blood–brain barrier. When the researchers tested brain tissue samples obtained from 20 human patients after death, they found more S1PR2 in patients with MS than in those without the disorder. Brain tissue from females also had higher levels of S1PR2, compared with male brain tissue. These findings may help explain why more women than men get the disease, said the authors.

The FDA has required the manufacturer of the sleep drug Lunesta (eszopiclone) to lower the recommended starting dose from 2 mg to 1 mg for men and women. Data show that eszopiclone levels in some patients may be high enough on the morning after treatment to impair activities that require alertness, including driving. The 1-mg dose, taken at bedtime, can be increased to 2 mg or 3 mg if needed, but the higher doses are more likely to result in next-day impairment. Using lower doses ensures that less drug will remain in the body during the morning hours. Patients currently taking the 2-mg and 3-mg doses of Lunesta should contact their health care professional to ask for instructions, according to the FDA.

The rate of visits to an emergency department (ED) for traumatic brain injury (TBI) increased by approximately 30% between 2006 and 2010, according to research published in the May 14 issue of JAMA. The increase may be attributable to various factors, including increased awareness and diagnoses, said the authors. The investigators examined data from the Nationwide Emergency Department Sample database to determine national trends in ED visits for TBI from 2006 through 2010. An estimated 2.5 million ED visits for TBI occurred in 2010, representing a 29% increase in the rate of visits for TBI during the study period. By comparison, total ED visits increased by 3.6%. Children younger than 3 and adults older than 60 had the largest increase in TBI rates.

The pathophysiologic biomarkers and the topographic markers of Alzheimer’s disease should be revised, according to a position paper by the International Working Group published in the June issue of Lancet Neurology. The group proposed that biomarkers of Alzheimer’s pathology be restricted to those indicating the presence of tau pathology (ie, CSF or PET tau) and amyloid pathology (ie, CSF or PET amyloid). These biomarkers are specific enough to diagnose Alzheimer’s disease at any point on the disease continuum, said the authors. Downstream topographic markers of brain regional structural and metabolic changes have insufficient pathologic specificity and should not be used in diagnosis, according to the researchers. Instead, these markers can be used to measure disease progression. The group also provided diagnostic criteria for atypical, mixed, and preclinical Alzheimer’s disease.

Prenatal supplementation with docosahexaenoic acid (DHA) does not result in improved cognitive, problem-solving, or language abilities for children at age 4, according to the results of a trial published in the May 7 issue of JAMA. Investigators conducted longer-term follow-up from a previous study in which pregnant women received 800 mg/day of DHA or placebo. In the initial study, the researchers found that average cognitive, language, and motor scores did not differ between children at 18 months of age. Approximately 92% of eligible families participated in the follow-up study. The DHA group included 313 participants, and the control group included 333 participants. The investigators found that measures of cognition, the ability to perform complex mental processing, language, and executive functioning (eg, memory, reasoning, and problem solving) did not differ significantly between groups at age 4.

The FDA has informed Acorda Therapeutics that it has completed its review of the company’s new drug application for Plumiaz (diazepam) nasal spray and that the application cannot be approved in its present form. The drug was developed for the treatment of people with epilepsy who experience cluster seizures. Acorda Therapeutics is developing a response to address the items outlined in the letter. Based on the requirements for approval outlined in the letter, the company does not expect Plumiaz to receive FDA approval in 2014. Plumiaz previously received orphan drug designation for the treatment of cluster seizures. [For related news, see page 9.]

Older people with memory and thinking problems who do not have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems, according to a study published April 22 in Neurology. Researchers studied 2,627 people age 65 and older who did not have dementia at baseline. Participants underwent tests of memory and thinking skills at baseline and at three years. Follow-up lasted for an average of approximately 13 years. During the study, 1,003 participants died. About 34% of deaths occurred among patients with the fastest decline in thinking skills. Approximately 21% of participants in the group with the fastest decline in thinking skills died of cancer, compared with 29% of participants in the other two groups.

A new technique may predict with 95% accuracy which patients with stroke will benefit from IV t-PA and which will have potentially lethal bleeding in the brain, according to a study published online ahead of print May 15 in Stroke. Researchers used a computer program that shows physicians the amount of gadolinium, injected during an MRI scan, that has leaked into the brain tissue from surrounding blood vessels. By quantifying this damage in 75 patients with stroke, the researchers identified a threshold for determining how much leakage was dangerous. They applied this threshold to the records for the 75 patients to determine how well it would predict who had had a brain hemorrhage and who had not. The new test correctly predicted the outcome with 95% accuracy.

Freezing of gait in patients with Parkinson’s disease may correlate with poor quality of life, disease severity, apathy, and exposure to antimuscarinics, according to a study published online ahead of print May 19 in JAMA Neurology. Investigators performed a cross-sectional survey of 672 patients with idiopathic Parkinson’s disease. Patients with freezing of gait were identified as those with a score of 1 or greater on item 14 of the Unified Parkinson’s Disease Rating Scale (UPDRS) in the on condition. Approximately 38% of patients reported freezing of gait during the on state, which was significantly related to lower quality of life scores. Freezing of gait was also correlated with longer disease duration, higher UPDRS parts II and III scores, apathy, and a higher levodopa equivalent daily dose.

Among college football players, concussion and years of football played may have a significant inverse relationship with hippocampal volume, according to research published May 14 in JAMA. Years of football experience also may correlate with slower reaction time. Investigators conducted a cross-sectional study of 25 college football players with a history of clinician-diagnosed concussion, 25 college football players without a history of concussion, and 25 nonfootball-playing, age-, sex-, and education-matched healthy controls. Players with and without a history of concussion had smaller hippocampal volumes, compared with healthy controls. Players with a history of concussion had smaller hippocampal volumes than players without concussion. In both athlete groups, investigators found a statistically significant inverse relationship between left hippocampal volume and number of years of football played.

Deficiencies in hyaluronan can lead to spontaneous epileptic seizures, according to research published April 30 in the Journal of Neuroscience. In a multicenter study, investigators examined the role of hyaluronan using mutant mice deficient in each of the three hyaluronan synthase genes (ie, Has1, Has2, Has3). The mutant mice were prone to epileptic seizures. In Has3(-/-) mice, this phenotype likely results from a reduction in the size of the brain extracellular space (ECS), said the researchers. Among the three Has knockout models, seizures were most prevalent in Has3(-/-) mice, which also had the greatest hyaluronan reduction in the hippocampus. The results provide the first direct evidence for the physiologic role of hyaluronan in the regulation of ECS volume, according to the investigators.

—Erik Greb

Older patients with migraine may be more likely to have silent brain injury than older patients without migraine, according to research published online ahead of print May 15 in Stroke. Researchers analyzed data from the Northern Manhattan Study, which quantified subclinical brain infarctions and white matter hyperintensity volumes among participants with migraine. Of the 546 participants analyzed, 41% were men, 65% were Hispanic, and mean age at MRI was 71. Patients with migraine had double the odds of subclinical brain infarction, compared with those reporting no migraine, after the investigators adjusted for sociodemographics and vascular risk factors. No association was observed between migraine with or without aura and white matter hyperintensity volume. Patients with migraine should not worry, because their risk of ischemic stroke is small, said the authors.

People who are exposed to paint, glue, or degreaser fumes at work may experience memory and thinking problems in retirement, according to a study published May 13 in Neurology. Researchers examined data for 2,143 retired utility workers who underwent cognitive testing in 2010. The authors assessed workers’ lifetime exposure to chlorinated solvents, petroleum solvents, and benzene using a job exposure matrix. Approximately 33% of participants were exposed to chlorinated solvents, 26% to benzene, and 25% to petroleum solvents. Workers highly exposed to chlorinated solvents were at risk of impairment on the Mini-Mental State Examination, the Digit Symbol Substitution Test, semantic fluency test, and the Trail Making Test B. Retirees at greatest risk for deficits had high lifetime exposure to solvents and were last exposed 12 to 30 years before testing.

Females susceptible to multiple sclerosis (MS) produce higher levels of the blood vessel receptor protein S1PR2 than males, according to data published online ahead of print May 8 in the Journal of Clinical Investigation. S1PR2 is present at high levels in the brain areas that MS typically damages. Investigators studied a mouse model of MS and found increased activity of S1PR2, which opens up the blood–brain barrier. When the researchers tested brain tissue samples obtained from 20 human patients after death, they found more S1PR2 in patients with MS than in those without the disorder. Brain tissue from females also had higher levels of S1PR2, compared with male brain tissue. These findings may help explain why more women than men get the disease, said the authors.

The FDA has required the manufacturer of the sleep drug Lunesta (eszopiclone) to lower the recommended starting dose from 2 mg to 1 mg for men and women. Data show that eszopiclone levels in some patients may be high enough on the morning after treatment to impair activities that require alertness, including driving. The 1-mg dose, taken at bedtime, can be increased to 2 mg or 3 mg if needed, but the higher doses are more likely to result in next-day impairment. Using lower doses ensures that less drug will remain in the body during the morning hours. Patients currently taking the 2-mg and 3-mg doses of Lunesta should contact their health care professional to ask for instructions, according to the FDA.

The rate of visits to an emergency department (ED) for traumatic brain injury (TBI) increased by approximately 30% between 2006 and 2010, according to research published in the May 14 issue of JAMA. The increase may be attributable to various factors, including increased awareness and diagnoses, said the authors. The investigators examined data from the Nationwide Emergency Department Sample database to determine national trends in ED visits for TBI from 2006 through 2010. An estimated 2.5 million ED visits for TBI occurred in 2010, representing a 29% increase in the rate of visits for TBI during the study period. By comparison, total ED visits increased by 3.6%. Children younger than 3 and adults older than 60 had the largest increase in TBI rates.

The pathophysiologic biomarkers and the topographic markers of Alzheimer’s disease should be revised, according to a position paper by the International Working Group published in the June issue of Lancet Neurology. The group proposed that biomarkers of Alzheimer’s pathology be restricted to those indicating the presence of tau pathology (ie, CSF or PET tau) and amyloid pathology (ie, CSF or PET amyloid). These biomarkers are specific enough to diagnose Alzheimer’s disease at any point on the disease continuum, said the authors. Downstream topographic markers of brain regional structural and metabolic changes have insufficient pathologic specificity and should not be used in diagnosis, according to the researchers. Instead, these markers can be used to measure disease progression. The group also provided diagnostic criteria for atypical, mixed, and preclinical Alzheimer’s disease.

Prenatal supplementation with docosahexaenoic acid (DHA) does not result in improved cognitive, problem-solving, or language abilities for children at age 4, according to the results of a trial published in the May 7 issue of JAMA. Investigators conducted longer-term follow-up from a previous study in which pregnant women received 800 mg/day of DHA or placebo. In the initial study, the researchers found that average cognitive, language, and motor scores did not differ between children at 18 months of age. Approximately 92% of eligible families participated in the follow-up study. The DHA group included 313 participants, and the control group included 333 participants. The investigators found that measures of cognition, the ability to perform complex mental processing, language, and executive functioning (eg, memory, reasoning, and problem solving) did not differ significantly between groups at age 4.

The FDA has informed Acorda Therapeutics that it has completed its review of the company’s new drug application for Plumiaz (diazepam) nasal spray and that the application cannot be approved in its present form. The drug was developed for the treatment of people with epilepsy who experience cluster seizures. Acorda Therapeutics is developing a response to address the items outlined in the letter. Based on the requirements for approval outlined in the letter, the company does not expect Plumiaz to receive FDA approval in 2014. Plumiaz previously received orphan drug designation for the treatment of cluster seizures. [For related news, see page 9.]

Older people with memory and thinking problems who do not have dementia may have a lower risk of dying from cancer than people who have no memory and thinking problems, according to a study published April 22 in Neurology. Researchers studied 2,627 people age 65 and older who did not have dementia at baseline. Participants underwent tests of memory and thinking skills at baseline and at three years. Follow-up lasted for an average of approximately 13 years. During the study, 1,003 participants died. About 34% of deaths occurred among patients with the fastest decline in thinking skills. Approximately 21% of participants in the group with the fastest decline in thinking skills died of cancer, compared with 29% of participants in the other two groups.

A new technique may predict with 95% accuracy which patients with stroke will benefit from IV t-PA and which will have potentially lethal bleeding in the brain, according to a study published online ahead of print May 15 in Stroke. Researchers used a computer program that shows physicians the amount of gadolinium, injected during an MRI scan, that has leaked into the brain tissue from surrounding blood vessels. By quantifying this damage in 75 patients with stroke, the researchers identified a threshold for determining how much leakage was dangerous. They applied this threshold to the records for the 75 patients to determine how well it would predict who had had a brain hemorrhage and who had not. The new test correctly predicted the outcome with 95% accuracy.

Freezing of gait in patients with Parkinson’s disease may correlate with poor quality of life, disease severity, apathy, and exposure to antimuscarinics, according to a study published online ahead of print May 19 in JAMA Neurology. Investigators performed a cross-sectional survey of 672 patients with idiopathic Parkinson’s disease. Patients with freezing of gait were identified as those with a score of 1 or greater on item 14 of the Unified Parkinson’s Disease Rating Scale (UPDRS) in the on condition. Approximately 38% of patients reported freezing of gait during the on state, which was significantly related to lower quality of life scores. Freezing of gait was also correlated with longer disease duration, higher UPDRS parts II and III scores, apathy, and a higher levodopa equivalent daily dose.

Among college football players, concussion and years of football played may have a significant inverse relationship with hippocampal volume, according to research published May 14 in JAMA. Years of football experience also may correlate with slower reaction time. Investigators conducted a cross-sectional study of 25 college football players with a history of clinician-diagnosed concussion, 25 college football players without a history of concussion, and 25 nonfootball-playing, age-, sex-, and education-matched healthy controls. Players with and without a history of concussion had smaller hippocampal volumes, compared with healthy controls. Players with a history of concussion had smaller hippocampal volumes than players without concussion. In both athlete groups, investigators found a statistically significant inverse relationship between left hippocampal volume and number of years of football played.

Deficiencies in hyaluronan can lead to spontaneous epileptic seizures, according to research published April 30 in the Journal of Neuroscience. In a multicenter study, investigators examined the role of hyaluronan using mutant mice deficient in each of the three hyaluronan synthase genes (ie, Has1, Has2, Has3). The mutant mice were prone to epileptic seizures. In Has3(-/-) mice, this phenotype likely results from a reduction in the size of the brain extracellular space (ECS), said the researchers. Among the three Has knockout models, seizures were most prevalent in Has3(-/-) mice, which also had the greatest hyaluronan reduction in the hippocampus. The results provide the first direct evidence for the physiologic role of hyaluronan in the regulation of ECS volume, according to the investigators.

—Erik Greb