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Zeroing in on Tuberous Sclerosis Complex
BOSTON—Patients with tuberous sclerosis complex (TSC) may benefit from novel therapies targeting idoleamine 2,3-dioxygenase (IDO) and major vault protein (MVP), researchers at Wayne State University in Detroit reported at the American Epilepsy Society meeting. Carlos Batista, a graduate student in the Translational Neuroscience Program, and colleagues studied cortical tubers that were surgically removed from 12 children with TSC and found elevated tryptophan metabolism and expressions of IDO and MVP.
“Cortical tubers express large numbers of activated microglia, macrophages, and T lymphocytes, thus suggesting activation of inflammatory pathways,” the researchers noted. “Under conditions that cause activation of inflammatory pathways, IDO (the rate-limiting enzyme of tryptophan metabolism by the kynurenine pathway in the brain) is induced by IFN-γ.”
Furthermore, MVP, which is associated with multidrug resistance, is also induced by IFN-γ. Researchers hypothesized and found that the effect of inflammation on MVP and IDO in epileptogenic tumors may be different in TSC1 and TSC2 mutations. Patients with TSC2 had a higher expression of MVP than those with TSC1, which may explain the more severe course of the disease in TSC2 patients.
BOSTON—Patients with tuberous sclerosis complex (TSC) may benefit from novel therapies targeting idoleamine 2,3-dioxygenase (IDO) and major vault protein (MVP), researchers at Wayne State University in Detroit reported at the American Epilepsy Society meeting. Carlos Batista, a graduate student in the Translational Neuroscience Program, and colleagues studied cortical tubers that were surgically removed from 12 children with TSC and found elevated tryptophan metabolism and expressions of IDO and MVP.
“Cortical tubers express large numbers of activated microglia, macrophages, and T lymphocytes, thus suggesting activation of inflammatory pathways,” the researchers noted. “Under conditions that cause activation of inflammatory pathways, IDO (the rate-limiting enzyme of tryptophan metabolism by the kynurenine pathway in the brain) is induced by IFN-γ.”
Furthermore, MVP, which is associated with multidrug resistance, is also induced by IFN-γ. Researchers hypothesized and found that the effect of inflammation on MVP and IDO in epileptogenic tumors may be different in TSC1 and TSC2 mutations. Patients with TSC2 had a higher expression of MVP than those with TSC1, which may explain the more severe course of the disease in TSC2 patients.
BOSTON—Patients with tuberous sclerosis complex (TSC) may benefit from novel therapies targeting idoleamine 2,3-dioxygenase (IDO) and major vault protein (MVP), researchers at Wayne State University in Detroit reported at the American Epilepsy Society meeting. Carlos Batista, a graduate student in the Translational Neuroscience Program, and colleagues studied cortical tubers that were surgically removed from 12 children with TSC and found elevated tryptophan metabolism and expressions of IDO and MVP.
“Cortical tubers express large numbers of activated microglia, macrophages, and T lymphocytes, thus suggesting activation of inflammatory pathways,” the researchers noted. “Under conditions that cause activation of inflammatory pathways, IDO (the rate-limiting enzyme of tryptophan metabolism by the kynurenine pathway in the brain) is induced by IFN-γ.”
Furthermore, MVP, which is associated with multidrug resistance, is also induced by IFN-γ. Researchers hypothesized and found that the effect of inflammation on MVP and IDO in epileptogenic tumors may be different in TSC1 and TSC2 mutations. Patients with TSC2 had a higher expression of MVP than those with TSC1, which may explain the more severe course of the disease in TSC2 patients.
News Roundup: New and Noteworthy Information
Women with Down syndrome who experienced early menopause were almost twice as likely to develop dementia at a younger age than those who entered menopause later, according to research in the January Journal of Alzheimer’s Disease. In a prospective longitudinal cohort study of dementia and mortality in women with Down syndrome, researchers followed 85 postmenopausal subjects for an average of 4.3 years and found a significant correlation between the age at menopause onset and age at diagnosis of dementia. Subjects with an earlier onset of menopause had a 1.8-fold increased risk of dementia. In addition, women who experienced menopause earlier had a twofold increased risk of dying younger.
White, elderly cancer survivors have a reduced risk of developing Alzheimer’s disease, as reported in the January 12 Neurology. Conversely, patients with Alzheimer’s disease have a reduced cancer risk, investigators found. In a prospective cohort study of 3,020 subjects ages 65 and older, the presence of Alzheimer’s disease was associated with a reduced risk of cancer hospitalizations, after adjustments for demographic and other factors. Prevalent cancer was also associated with a reduced risk of Alzheimer’s disease among white subjects after the researchers adjusted for demographics, number of apolipoprotein ε4 alleles, hypertension, diabetes, and coronary heart disease. The opposite was found in minorities, although the sample size was considered too small. No significant association was found between cancer and vascular dementia.
Ginkgo biloba did not preserve cognitive function any better than a placebo, per a study in the December 23, 2009, JAMA. In the randomized, double-blind, placebo-controlled Ginkgo Evaluation of Memory study, researchers at six academic medical centers in the US tracked 3,069 community-dwelling subjects ages 72 to 96 years for an average of 6.1 years. Subjects were given either a twice-daily dose of 120 mg extract of Ginkgo biloba or a placebo. Cognition was measured as rates of change over time in the Modified Mini-Mental State Examination, the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and neuropsychologic domains of memory, attention, visual-spatial construction, language, and executive functions. Investigators found no significant difference in cognitive decline between the herb and placebo.
A decreased ability to smell is common in patients with Alzheimer’s disease and may be a useful early diagnostic tool, researchers reported in the January 13 Journal of Neuroscience. The study linked olfactory dysfunction with an accumulation of amyloid-β protein in Alzheimer’s disease model mice. “The usefulness of olfactory screens to serve as informative indicators of Alzheimer’s is precluded by a lack of knowledge regarding why the disease impacts olfaction,” the study authors stated. The investigators assayed olfactory perception and amyloid-β deposition in the genetically engineered mice and found that amyloid-β pathology first occurred in an area of the brain responsible for smelling. Mice with higher concentrations of amyloid-β also displayed olfactory dysfunction. Researchers noted the “odor cross-habitation test [was] a powerful behavioral assay…[which] may serve to monitor the efficacy of therapies aimed at reducing amyloid-β.”
The Lancet has retracted the 1998 paper by Wakefield et al that suggested a link between autism and the childhood measles, mumps, and rubella (MMR) vaccine. The retraction, published in the February 2 online issue, follows a judgment by the UK General Medical Council’s Fitness to Practice Panel on January 28. “It has become clear that several elements of the 1998 paper by Wakefield et al are incorrect,” the editors wrote. “In particular, the claims in the original paper that children were ‘consecutively referred’ and that investigations were ‘approved’ by the local ethics committee have been proven to be false.” In 2004, 10 of the original authors retracted parts of the study, stating, “in this paper no causal link was established between MMR vaccine and autism as the data were insufficient.”
Advanced maternal age may be linked to an increased risk of autism, researchers reported in the February 8 online Autism Research. In a study of 12,159 cases of autism from a pool of almost 5 million births between 1990 and 1999, the investigators found a monotonic increased risk of autism related to advancing maternal age (40 and older) regardless of paternal age. However, the study authors noted fathers aged 40 and up who mated with women younger than 30 also had an increased risk of autistic offspring, compared with men in their mid- to late-20s. Yet when the mother was older than 30 and the father was 40 or older, the associated autism risk was similar to that of younger men. The investigators also noted that the “recent trend towards delaying childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.”
Depression and migraine headaches appear to share a common genetic factor, a Dutch study of 2,652 people found. As reported in the January 26 Neurology, researchers compared heritability estimates among members of the Erasmus Rucphen family for migraine with and without depression, and depression rates between migraineurs and controls. Of the total study population, 360 had migraines, 151 of whom experienced migraine aura as well. One-quarter of migraineurs also had depression, compared with 13% of the controls. Odds ratios for depression in patients with migraine were 1.29 for those without aura and 1.70 for those with aura. “There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors,” the study authors noted.
The FDA has approved Ampyra (dalfampridine) extended-release tablets to improve walking in patients with multiple sclerosis (MS). In clinical trials, patients treated with dalfampridine had faster walking speeds than those treated with a placebo. It is the first report in which a drug for MS improved function that was lost as a result of the disease. The most common side effects reported were urinary tract infection, insomnia, dizziness, headache, nausea, and others. When taken in doses greater than 10 mg twice a day, seizures may occur. It should not be used in patients with moderate to severe kidney disease. Dalfampridine is distributed by Acorda Therapeutics Inc of Hawthorne, New York.
Black patients with multiple sclerosis showed increased tissue damage and higher lesion volumes compared with white patients, according to research in the February 16 Neurology. In a study of 567 patients, 488 of whom were white and 79 were black, investigators compared quantitative MRI evaluations including T1-, T2-, and gadolinium contrast-enhancing lesion volumes and contrast-enhancing number, global and tissue-specific brain atrophy, and magnetization transfer ratios (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The researchers found that MTR values in lesions and in NAGM and NAWM were significantly lower in black subjects than in whites, and T1- and T2- lesion volumes were greater, both of which indicate a more aggressive clinical disease.
Dopamine agonists can cause or exacerbate compulsive behaviors in patients with Parkinson’s, according to research published in the January 14 Neuron. “A constellation of pathological behaviors, including gambling, shopping, binge eating, and hypersexuality is seen in 17% of patients on dopamine agonists,” the study authors wrote. Because reinforcement learning algorithms allow for computation of prediction error, the researchers used a reinforcement learning model to deconstruct decision-making processes dysregulated by dopamine agonists in patients who are susceptible to compulsive behaviors. The investigators found that the medications increased the rate of learning from gain outcomes and increased striatal prediction error activity, signifying a “better than expected” outcome.
Patients with acute ischemic stroke admitted to the hospital on the weekend are more likely to receive t-PA than those admitted on a weekday, a study in the January Archives of Neurology reported. Researchers analyzed rates of t-PA administration, as well as death rates, among 78,657stroke patients admitted to Virginia hospitals between 1998 and 2006 and found weekend patients (n=20,279) were 20% more likely to receive t-PA than weekday patients (n=58,378). There was no statistically significant difference in patient mortality based on day of admission; however, because a greater percentage of weekend patients received t-PA while death rates remained equal, the study authors noted that those treated with t-PA may be more likely to die in the hospital.
Impaired cognitive function in elderly men may be an independent predictor of subsequent stroke, according to a report in the February 2 Neurology. In a study of 930 elderly men (mean age, 70), Swedish researchers found that taking longer to complete the Trail Making Test B increased stroke risk by as much as 300% for those in the highest quartile, compared with those in the lowest quartile. Each time increase of 1 SD was associated with a 1.48 higher risk of stroke. “Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit,” the study authors wrote.
Women with Down syndrome who experienced early menopause were almost twice as likely to develop dementia at a younger age than those who entered menopause later, according to research in the January Journal of Alzheimer’s Disease. In a prospective longitudinal cohort study of dementia and mortality in women with Down syndrome, researchers followed 85 postmenopausal subjects for an average of 4.3 years and found a significant correlation between the age at menopause onset and age at diagnosis of dementia. Subjects with an earlier onset of menopause had a 1.8-fold increased risk of dementia. In addition, women who experienced menopause earlier had a twofold increased risk of dying younger.
White, elderly cancer survivors have a reduced risk of developing Alzheimer’s disease, as reported in the January 12 Neurology. Conversely, patients with Alzheimer’s disease have a reduced cancer risk, investigators found. In a prospective cohort study of 3,020 subjects ages 65 and older, the presence of Alzheimer’s disease was associated with a reduced risk of cancer hospitalizations, after adjustments for demographic and other factors. Prevalent cancer was also associated with a reduced risk of Alzheimer’s disease among white subjects after the researchers adjusted for demographics, number of apolipoprotein ε4 alleles, hypertension, diabetes, and coronary heart disease. The opposite was found in minorities, although the sample size was considered too small. No significant association was found between cancer and vascular dementia.
Ginkgo biloba did not preserve cognitive function any better than a placebo, per a study in the December 23, 2009, JAMA. In the randomized, double-blind, placebo-controlled Ginkgo Evaluation of Memory study, researchers at six academic medical centers in the US tracked 3,069 community-dwelling subjects ages 72 to 96 years for an average of 6.1 years. Subjects were given either a twice-daily dose of 120 mg extract of Ginkgo biloba or a placebo. Cognition was measured as rates of change over time in the Modified Mini-Mental State Examination, the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and neuropsychologic domains of memory, attention, visual-spatial construction, language, and executive functions. Investigators found no significant difference in cognitive decline between the herb and placebo.
A decreased ability to smell is common in patients with Alzheimer’s disease and may be a useful early diagnostic tool, researchers reported in the January 13 Journal of Neuroscience. The study linked olfactory dysfunction with an accumulation of amyloid-β protein in Alzheimer’s disease model mice. “The usefulness of olfactory screens to serve as informative indicators of Alzheimer’s is precluded by a lack of knowledge regarding why the disease impacts olfaction,” the study authors stated. The investigators assayed olfactory perception and amyloid-β deposition in the genetically engineered mice and found that amyloid-β pathology first occurred in an area of the brain responsible for smelling. Mice with higher concentrations of amyloid-β also displayed olfactory dysfunction. Researchers noted the “odor cross-habitation test [was] a powerful behavioral assay…[which] may serve to monitor the efficacy of therapies aimed at reducing amyloid-β.”
The Lancet has retracted the 1998 paper by Wakefield et al that suggested a link between autism and the childhood measles, mumps, and rubella (MMR) vaccine. The retraction, published in the February 2 online issue, follows a judgment by the UK General Medical Council’s Fitness to Practice Panel on January 28. “It has become clear that several elements of the 1998 paper by Wakefield et al are incorrect,” the editors wrote. “In particular, the claims in the original paper that children were ‘consecutively referred’ and that investigations were ‘approved’ by the local ethics committee have been proven to be false.” In 2004, 10 of the original authors retracted parts of the study, stating, “in this paper no causal link was established between MMR vaccine and autism as the data were insufficient.”
Advanced maternal age may be linked to an increased risk of autism, researchers reported in the February 8 online Autism Research. In a study of 12,159 cases of autism from a pool of almost 5 million births between 1990 and 1999, the investigators found a monotonic increased risk of autism related to advancing maternal age (40 and older) regardless of paternal age. However, the study authors noted fathers aged 40 and up who mated with women younger than 30 also had an increased risk of autistic offspring, compared with men in their mid- to late-20s. Yet when the mother was older than 30 and the father was 40 or older, the associated autism risk was similar to that of younger men. The investigators also noted that the “recent trend towards delaying childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.”
Depression and migraine headaches appear to share a common genetic factor, a Dutch study of 2,652 people found. As reported in the January 26 Neurology, researchers compared heritability estimates among members of the Erasmus Rucphen family for migraine with and without depression, and depression rates between migraineurs and controls. Of the total study population, 360 had migraines, 151 of whom experienced migraine aura as well. One-quarter of migraineurs also had depression, compared with 13% of the controls. Odds ratios for depression in patients with migraine were 1.29 for those without aura and 1.70 for those with aura. “There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors,” the study authors noted.
The FDA has approved Ampyra (dalfampridine) extended-release tablets to improve walking in patients with multiple sclerosis (MS). In clinical trials, patients treated with dalfampridine had faster walking speeds than those treated with a placebo. It is the first report in which a drug for MS improved function that was lost as a result of the disease. The most common side effects reported were urinary tract infection, insomnia, dizziness, headache, nausea, and others. When taken in doses greater than 10 mg twice a day, seizures may occur. It should not be used in patients with moderate to severe kidney disease. Dalfampridine is distributed by Acorda Therapeutics Inc of Hawthorne, New York.
Black patients with multiple sclerosis showed increased tissue damage and higher lesion volumes compared with white patients, according to research in the February 16 Neurology. In a study of 567 patients, 488 of whom were white and 79 were black, investigators compared quantitative MRI evaluations including T1-, T2-, and gadolinium contrast-enhancing lesion volumes and contrast-enhancing number, global and tissue-specific brain atrophy, and magnetization transfer ratios (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The researchers found that MTR values in lesions and in NAGM and NAWM were significantly lower in black subjects than in whites, and T1- and T2- lesion volumes were greater, both of which indicate a more aggressive clinical disease.
Dopamine agonists can cause or exacerbate compulsive behaviors in patients with Parkinson’s, according to research published in the January 14 Neuron. “A constellation of pathological behaviors, including gambling, shopping, binge eating, and hypersexuality is seen in 17% of patients on dopamine agonists,” the study authors wrote. Because reinforcement learning algorithms allow for computation of prediction error, the researchers used a reinforcement learning model to deconstruct decision-making processes dysregulated by dopamine agonists in patients who are susceptible to compulsive behaviors. The investigators found that the medications increased the rate of learning from gain outcomes and increased striatal prediction error activity, signifying a “better than expected” outcome.
Patients with acute ischemic stroke admitted to the hospital on the weekend are more likely to receive t-PA than those admitted on a weekday, a study in the January Archives of Neurology reported. Researchers analyzed rates of t-PA administration, as well as death rates, among 78,657stroke patients admitted to Virginia hospitals between 1998 and 2006 and found weekend patients (n=20,279) were 20% more likely to receive t-PA than weekday patients (n=58,378). There was no statistically significant difference in patient mortality based on day of admission; however, because a greater percentage of weekend patients received t-PA while death rates remained equal, the study authors noted that those treated with t-PA may be more likely to die in the hospital.
Impaired cognitive function in elderly men may be an independent predictor of subsequent stroke, according to a report in the February 2 Neurology. In a study of 930 elderly men (mean age, 70), Swedish researchers found that taking longer to complete the Trail Making Test B increased stroke risk by as much as 300% for those in the highest quartile, compared with those in the lowest quartile. Each time increase of 1 SD was associated with a 1.48 higher risk of stroke. “Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit,” the study authors wrote.
Women with Down syndrome who experienced early menopause were almost twice as likely to develop dementia at a younger age than those who entered menopause later, according to research in the January Journal of Alzheimer’s Disease. In a prospective longitudinal cohort study of dementia and mortality in women with Down syndrome, researchers followed 85 postmenopausal subjects for an average of 4.3 years and found a significant correlation between the age at menopause onset and age at diagnosis of dementia. Subjects with an earlier onset of menopause had a 1.8-fold increased risk of dementia. In addition, women who experienced menopause earlier had a twofold increased risk of dying younger.
White, elderly cancer survivors have a reduced risk of developing Alzheimer’s disease, as reported in the January 12 Neurology. Conversely, patients with Alzheimer’s disease have a reduced cancer risk, investigators found. In a prospective cohort study of 3,020 subjects ages 65 and older, the presence of Alzheimer’s disease was associated with a reduced risk of cancer hospitalizations, after adjustments for demographic and other factors. Prevalent cancer was also associated with a reduced risk of Alzheimer’s disease among white subjects after the researchers adjusted for demographics, number of apolipoprotein ε4 alleles, hypertension, diabetes, and coronary heart disease. The opposite was found in minorities, although the sample size was considered too small. No significant association was found between cancer and vascular dementia.
Ginkgo biloba did not preserve cognitive function any better than a placebo, per a study in the December 23, 2009, JAMA. In the randomized, double-blind, placebo-controlled Ginkgo Evaluation of Memory study, researchers at six academic medical centers in the US tracked 3,069 community-dwelling subjects ages 72 to 96 years for an average of 6.1 years. Subjects were given either a twice-daily dose of 120 mg extract of Ginkgo biloba or a placebo. Cognition was measured as rates of change over time in the Modified Mini-Mental State Examination, the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and neuropsychologic domains of memory, attention, visual-spatial construction, language, and executive functions. Investigators found no significant difference in cognitive decline between the herb and placebo.
A decreased ability to smell is common in patients with Alzheimer’s disease and may be a useful early diagnostic tool, researchers reported in the January 13 Journal of Neuroscience. The study linked olfactory dysfunction with an accumulation of amyloid-β protein in Alzheimer’s disease model mice. “The usefulness of olfactory screens to serve as informative indicators of Alzheimer’s is precluded by a lack of knowledge regarding why the disease impacts olfaction,” the study authors stated. The investigators assayed olfactory perception and amyloid-β deposition in the genetically engineered mice and found that amyloid-β pathology first occurred in an area of the brain responsible for smelling. Mice with higher concentrations of amyloid-β also displayed olfactory dysfunction. Researchers noted the “odor cross-habitation test [was] a powerful behavioral assay…[which] may serve to monitor the efficacy of therapies aimed at reducing amyloid-β.”
The Lancet has retracted the 1998 paper by Wakefield et al that suggested a link between autism and the childhood measles, mumps, and rubella (MMR) vaccine. The retraction, published in the February 2 online issue, follows a judgment by the UK General Medical Council’s Fitness to Practice Panel on January 28. “It has become clear that several elements of the 1998 paper by Wakefield et al are incorrect,” the editors wrote. “In particular, the claims in the original paper that children were ‘consecutively referred’ and that investigations were ‘approved’ by the local ethics committee have been proven to be false.” In 2004, 10 of the original authors retracted parts of the study, stating, “in this paper no causal link was established between MMR vaccine and autism as the data were insufficient.”
Advanced maternal age may be linked to an increased risk of autism, researchers reported in the February 8 online Autism Research. In a study of 12,159 cases of autism from a pool of almost 5 million births between 1990 and 1999, the investigators found a monotonic increased risk of autism related to advancing maternal age (40 and older) regardless of paternal age. However, the study authors noted fathers aged 40 and up who mated with women younger than 30 also had an increased risk of autistic offspring, compared with men in their mid- to late-20s. Yet when the mother was older than 30 and the father was 40 or older, the associated autism risk was similar to that of younger men. The investigators also noted that the “recent trend towards delaying childbearing contributed approximately a 4.6% increase in autism diagnoses in California over the decade.”
Depression and migraine headaches appear to share a common genetic factor, a Dutch study of 2,652 people found. As reported in the January 26 Neurology, researchers compared heritability estimates among members of the Erasmus Rucphen family for migraine with and without depression, and depression rates between migraineurs and controls. Of the total study population, 360 had migraines, 151 of whom experienced migraine aura as well. One-quarter of migraineurs also had depression, compared with 13% of the controls. Odds ratios for depression in patients with migraine were 1.29 for those without aura and 1.70 for those with aura. “There is a bidirectional association between depression and migraine, in particular migraine with aura, which can be explained, at least partly, by shared genetic factors,” the study authors noted.
The FDA has approved Ampyra (dalfampridine) extended-release tablets to improve walking in patients with multiple sclerosis (MS). In clinical trials, patients treated with dalfampridine had faster walking speeds than those treated with a placebo. It is the first report in which a drug for MS improved function that was lost as a result of the disease. The most common side effects reported were urinary tract infection, insomnia, dizziness, headache, nausea, and others. When taken in doses greater than 10 mg twice a day, seizures may occur. It should not be used in patients with moderate to severe kidney disease. Dalfampridine is distributed by Acorda Therapeutics Inc of Hawthorne, New York.
Black patients with multiple sclerosis showed increased tissue damage and higher lesion volumes compared with white patients, according to research in the February 16 Neurology. In a study of 567 patients, 488 of whom were white and 79 were black, investigators compared quantitative MRI evaluations including T1-, T2-, and gadolinium contrast-enhancing lesion volumes and contrast-enhancing number, global and tissue-specific brain atrophy, and magnetization transfer ratios (MTR) in lesions and normal-appearing gray matter (NAGM) and white matter (NAWM). The researchers found that MTR values in lesions and in NAGM and NAWM were significantly lower in black subjects than in whites, and T1- and T2- lesion volumes were greater, both of which indicate a more aggressive clinical disease.
Dopamine agonists can cause or exacerbate compulsive behaviors in patients with Parkinson’s, according to research published in the January 14 Neuron. “A constellation of pathological behaviors, including gambling, shopping, binge eating, and hypersexuality is seen in 17% of patients on dopamine agonists,” the study authors wrote. Because reinforcement learning algorithms allow for computation of prediction error, the researchers used a reinforcement learning model to deconstruct decision-making processes dysregulated by dopamine agonists in patients who are susceptible to compulsive behaviors. The investigators found that the medications increased the rate of learning from gain outcomes and increased striatal prediction error activity, signifying a “better than expected” outcome.
Patients with acute ischemic stroke admitted to the hospital on the weekend are more likely to receive t-PA than those admitted on a weekday, a study in the January Archives of Neurology reported. Researchers analyzed rates of t-PA administration, as well as death rates, among 78,657stroke patients admitted to Virginia hospitals between 1998 and 2006 and found weekend patients (n=20,279) were 20% more likely to receive t-PA than weekday patients (n=58,378). There was no statistically significant difference in patient mortality based on day of admission; however, because a greater percentage of weekend patients received t-PA while death rates remained equal, the study authors noted that those treated with t-PA may be more likely to die in the hospital.
Impaired cognitive function in elderly men may be an independent predictor of subsequent stroke, according to a report in the February 2 Neurology. In a study of 930 elderly men (mean age, 70), Swedish researchers found that taking longer to complete the Trail Making Test B increased stroke risk by as much as 300% for those in the highest quartile, compared with those in the lowest quartile. Each time increase of 1 SD was associated with a 1.48 higher risk of stroke. “Our results extend previous findings of cognitive decline as an independent predictor of stroke and indicate that the risk of brain infarction is increased already in the subclinical phase of cognitive deficit,” the study authors wrote.
Conference News Update
25th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), Dusseldorf, Germany
Fewer Injection Site Reactions Occur in Patients Using Interferon Beta-1a IM
Data from an observational phase IV study of 499 patients—the Swiss MS Skin Project—showed that patients with multiple sclerosis (MS) taking interferon beta-1a IM reported significantly fewer injection site reactions, compared with patients who took interferon beta-1b, glatiramer acetate, or interferon beta-1a. The study also found that patients taking interferon beta-1a IM were less likely to have missed a dose due to an injection site reaction in the four weeks prior to first assessment than those patients on other interferon therapies.
“This study showed that treatment with interferon beta-1a IM leads to fewer injection site reactions, which is an important factor in improving compliance,” said Karsten Beer, lead investigator for the study and a private neurologist in Wil, Switzerland. “As the only once-weekly injection treatment, interferon beta-1a IM offers people with relapsing MS an easy-to-use and highly effective treatment option. Convenience of an MS therapy is an important consideration for patients, as they do not want a therapy that will interfere with their daily lives.”
The Swiss MS Skin Project was designed to determine the frequency of injection site reactions, including skin necrosis and lipoatrophy, in patients taking interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a. Injection site reactions are believed to reduce treatment compliance among patients. The study enrolled nearly 500 patients on interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a for a minimum of two years (mean treatment duration, 5.9 years) and followed patients for one year.
At the first assessment, significantly fewer patients who took interferon beta-1a IM experienced injection site reactions (13.4% vs 57.7% of those who used interferon beta-1b, 30.4% for glatiramer acetate, and 67.9% for interferon beta-1a); necrosis (0% vs 5.7% for interferon beta-1b, 0% for glatiramer acetate, and 6.0% for interferon beta-1a); and lipoatrophy (1.2 % vs 8.9% for interferon beta-1b, 13.0% for glatiramer acetate, and 10.3% for interferon beta-1a).
No patients who used interferon beta-1a IM missed a dose in the four weeks prior to first assessment due to injection site reactions (vs 5.7% of patients using interferon beta-1b, 4.3% for glatiramer acetate, and 7.1% for interferon beta-1a). These percentages were statistically significant, compared with use of interferon beta-1b and interferon beta-1a. In addition, significantly more patients remained on interferon beta-1a IM throughout the one-year trial (86.6% vs 79.7% of subjects who used interferon beta-1b, 60.9% for glatiramer acetate, and 83.2% for interferon beta-1a) than on any other treatment.
Patients Taking Natalizumab Report Improvement in Physical and Psychologic Well-Being
Patients with multiple sclerosis (MS) taking natalizumab experienced an improvement in both their physical function and psychologic well-being, according to six-month results of an ongoing, one-year longitudinal, observational, patient-reported outcomes study. The study, which was the first to assess patient experiences with natalizumab in usual-care settings, found that patients who used natalizumab reported an improvement in their overall quality of life.
“The symptoms that a patient with MS deals with on a daily basis result in significant psychologic and physical effects that can adversely impact their quality of life,” said William Stuart, MD, Medical Director of the Multiple Sclerosis Center of Atlanta. “In a previous pivotal trial, natalizumab not only showed a reduction in relapse rates and disability progression, but also improved quality of life. Results from this observational study further demonstrate the impact of natalizumab on improving MS patients’ well-being as reported by patients who live with this disease every day.”
The trial assessed health outcomes from patients’ perspectives before starting natalizumab and after the third, sixth, and 12th infusions of the drug. A majority of the patients in the study are female (76.3%), with a mean age of 46.6 and mean disease duration of 10 years.
After six natalizumab infusions, patients reported statistically significant improvement in disease-specific quality of life, measured with use of the MS Impact Scale-29 (MSIS-29), which assesses the physical impact of MS in terms of mobility and self-care, as well as the psychologic impact of MS in terms of anxiety/depression, with lower scores indicating better quality of life. Patients also reported statistically significant improvement in general health-related quality of life, as measured by the 12-item Short Form Scale (SF-12) health survey, which assesses the physical and mental health, with higher scores indicating better quality of life.
Both scales assess patient experience of the physical and psychologic aspects of quality of life. For the MSIS-29 subscales, statistically significant improvements were observed over time for both the physical (baseline, 46.87; third infusion, 39.60; sixth infusion, 39.27) and psychologic (baseline, 41.56; third infusion, 33.77; sixth infusion, 33.20) impact scores.
SF-12 physical component summary score (baseline, 34.20; third infusion, 36.05; sixth infusion, 36.34) and the SF-12 mental component summary score (baseline, 43.25; third infusion, 47.35; sixth infusion, 47.92) showed statistically significant improvements over time.
[Editor’s note: For more information on natalizumab, please see a related news story and commentary on page 5.]
Genetic Targets for Potential MS Therapies
Two genes in mice were associated with good CNS repair in multiple sclerosis (MS). The findings may help researchers develop more effective therapies and predict outcomes for patients with MS.
“Most MS genetic studies have looked at disease susceptibility—or why some people get MS and others do not,” said Allan Bieber, PhD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota. “This study asked, among those who have MS, why some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome.”
Dr. Bieber and a team of Mayo Clinic researchers used two different strains of mice with a chronic, progressive MS-like disease. One strain of mice progressed to paralysis and death. The other strain underwent the initial damage induction phase of the disease and then had spontaneous repair of the damage to the CNS and retained most neurologic function. Using the genetic mapping techniques that are available for mice, the team mapped two strong genetic determinants of good disease outcome.
“It’s possible that the identification of these genes may provide the first important clue as to why some patients with MS do well, while others do not,” said Dr. Bieber. “The genetic data indicate that good CNS repair results from stimulation of one genetic pathway and inhibition of another genetic pathway. While we’re still in the early stages of this research, it could eventually lead to the development of useful therapies that stimulate or inhibit these genetic pathways in patients with MS.”
According to Dr. Bieber, the research suggests that there may be a small number of strong genetic determinants for CNS repair following demyelinating disease, rather than a larger number of weak determinants.
“If that’s true, it may be possible to map the most important genetic determinants of CNS repair in patients with MS and define a reparative genotype that could predict patients’ outcomes,” said Moses Rodriguez, MD, Professor of Neurology and Director of the Mayo Clinic’s Center for Multiple Sclerosis and Central Nervous System Demyelinating Diseases Research and Therapeutics. “Such a diagnostic tool would be a great benefit to patients with MS and is consistent with the concepts of individualized medicine.”
Research Supports the Importance of Early Treatment in Patients With MS
Findings from two observational studies—CogniCIS and CogniMS—revealed that depression and fatigue occur alongside cognitive deficits, even early in the disease. Data from these studies showed that relatives were able to detect even minor changes in cognitive performance at an early stage of the disease, which the patients themselves did not report.
“Cognitive impairment in patients with multiple sclerosis (MS) is not sufficiently recognized, in spite of the significant negative impact it can have on patients’ lives,” said Dawn Langdon, PhD, Neuropsychology Lead and Reader in Neuropsychology, Royal Holloway, University of London, UK, and lead investigator of CogniCIS and CogniMS. “These studies will help us construct a more complete picture of the development and impact of cognitive decline in early MS. Such findings, added to the existing evidence, will have important implications for physicians when making management decisions.”
The CogniCIS study collected cognitive and psychosocial data from 394 patients with clinically isolated syndrome (CIS). A subset of 130 European patients with CIS and 60 of their relatives completed the MS Neuropsychological Questionnaire (MSNQ), which asks about cognitive difficulties. Preliminary results presented showed that scores on the MSNQ from patients with CIS and their relatives correlated more with the patients’ level of depression, fatigue, and quality of life rather than performance in cognitive tests.
The CogniMS study included psychosocial data from 1,509 patients with early MS. A subset of 274 patients and 178 of their relatives completed the MSNQ. According to preliminary findings from the trial, relatives’ reports of the patients’ cognition correlated with some cognitive test scores, obtained by patients; patient self-reported cognitive deficits were not closely related to objective test scores. Similar to results from CogniCIS, the CogniMS findings suggest that self-reported cognitive deficits in an early MS population are not specific to cognition, and are influenced by the patients’ psychologic situation.
25th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), Dusseldorf, Germany
Fewer Injection Site Reactions Occur in Patients Using Interferon Beta-1a IM
Data from an observational phase IV study of 499 patients—the Swiss MS Skin Project—showed that patients with multiple sclerosis (MS) taking interferon beta-1a IM reported significantly fewer injection site reactions, compared with patients who took interferon beta-1b, glatiramer acetate, or interferon beta-1a. The study also found that patients taking interferon beta-1a IM were less likely to have missed a dose due to an injection site reaction in the four weeks prior to first assessment than those patients on other interferon therapies.
“This study showed that treatment with interferon beta-1a IM leads to fewer injection site reactions, which is an important factor in improving compliance,” said Karsten Beer, lead investigator for the study and a private neurologist in Wil, Switzerland. “As the only once-weekly injection treatment, interferon beta-1a IM offers people with relapsing MS an easy-to-use and highly effective treatment option. Convenience of an MS therapy is an important consideration for patients, as they do not want a therapy that will interfere with their daily lives.”
The Swiss MS Skin Project was designed to determine the frequency of injection site reactions, including skin necrosis and lipoatrophy, in patients taking interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a. Injection site reactions are believed to reduce treatment compliance among patients. The study enrolled nearly 500 patients on interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a for a minimum of two years (mean treatment duration, 5.9 years) and followed patients for one year.
At the first assessment, significantly fewer patients who took interferon beta-1a IM experienced injection site reactions (13.4% vs 57.7% of those who used interferon beta-1b, 30.4% for glatiramer acetate, and 67.9% for interferon beta-1a); necrosis (0% vs 5.7% for interferon beta-1b, 0% for glatiramer acetate, and 6.0% for interferon beta-1a); and lipoatrophy (1.2 % vs 8.9% for interferon beta-1b, 13.0% for glatiramer acetate, and 10.3% for interferon beta-1a).
No patients who used interferon beta-1a IM missed a dose in the four weeks prior to first assessment due to injection site reactions (vs 5.7% of patients using interferon beta-1b, 4.3% for glatiramer acetate, and 7.1% for interferon beta-1a). These percentages were statistically significant, compared with use of interferon beta-1b and interferon beta-1a. In addition, significantly more patients remained on interferon beta-1a IM throughout the one-year trial (86.6% vs 79.7% of subjects who used interferon beta-1b, 60.9% for glatiramer acetate, and 83.2% for interferon beta-1a) than on any other treatment.
Patients Taking Natalizumab Report Improvement in Physical and Psychologic Well-Being
Patients with multiple sclerosis (MS) taking natalizumab experienced an improvement in both their physical function and psychologic well-being, according to six-month results of an ongoing, one-year longitudinal, observational, patient-reported outcomes study. The study, which was the first to assess patient experiences with natalizumab in usual-care settings, found that patients who used natalizumab reported an improvement in their overall quality of life.
“The symptoms that a patient with MS deals with on a daily basis result in significant psychologic and physical effects that can adversely impact their quality of life,” said William Stuart, MD, Medical Director of the Multiple Sclerosis Center of Atlanta. “In a previous pivotal trial, natalizumab not only showed a reduction in relapse rates and disability progression, but also improved quality of life. Results from this observational study further demonstrate the impact of natalizumab on improving MS patients’ well-being as reported by patients who live with this disease every day.”
The trial assessed health outcomes from patients’ perspectives before starting natalizumab and after the third, sixth, and 12th infusions of the drug. A majority of the patients in the study are female (76.3%), with a mean age of 46.6 and mean disease duration of 10 years.
After six natalizumab infusions, patients reported statistically significant improvement in disease-specific quality of life, measured with use of the MS Impact Scale-29 (MSIS-29), which assesses the physical impact of MS in terms of mobility and self-care, as well as the psychologic impact of MS in terms of anxiety/depression, with lower scores indicating better quality of life. Patients also reported statistically significant improvement in general health-related quality of life, as measured by the 12-item Short Form Scale (SF-12) health survey, which assesses the physical and mental health, with higher scores indicating better quality of life.
Both scales assess patient experience of the physical and psychologic aspects of quality of life. For the MSIS-29 subscales, statistically significant improvements were observed over time for both the physical (baseline, 46.87; third infusion, 39.60; sixth infusion, 39.27) and psychologic (baseline, 41.56; third infusion, 33.77; sixth infusion, 33.20) impact scores.
SF-12 physical component summary score (baseline, 34.20; third infusion, 36.05; sixth infusion, 36.34) and the SF-12 mental component summary score (baseline, 43.25; third infusion, 47.35; sixth infusion, 47.92) showed statistically significant improvements over time.
[Editor’s note: For more information on natalizumab, please see a related news story and commentary on page 5.]
Genetic Targets for Potential MS Therapies
Two genes in mice were associated with good CNS repair in multiple sclerosis (MS). The findings may help researchers develop more effective therapies and predict outcomes for patients with MS.
“Most MS genetic studies have looked at disease susceptibility—or why some people get MS and others do not,” said Allan Bieber, PhD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota. “This study asked, among those who have MS, why some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome.”
Dr. Bieber and a team of Mayo Clinic researchers used two different strains of mice with a chronic, progressive MS-like disease. One strain of mice progressed to paralysis and death. The other strain underwent the initial damage induction phase of the disease and then had spontaneous repair of the damage to the CNS and retained most neurologic function. Using the genetic mapping techniques that are available for mice, the team mapped two strong genetic determinants of good disease outcome.
“It’s possible that the identification of these genes may provide the first important clue as to why some patients with MS do well, while others do not,” said Dr. Bieber. “The genetic data indicate that good CNS repair results from stimulation of one genetic pathway and inhibition of another genetic pathway. While we’re still in the early stages of this research, it could eventually lead to the development of useful therapies that stimulate or inhibit these genetic pathways in patients with MS.”
According to Dr. Bieber, the research suggests that there may be a small number of strong genetic determinants for CNS repair following demyelinating disease, rather than a larger number of weak determinants.
“If that’s true, it may be possible to map the most important genetic determinants of CNS repair in patients with MS and define a reparative genotype that could predict patients’ outcomes,” said Moses Rodriguez, MD, Professor of Neurology and Director of the Mayo Clinic’s Center for Multiple Sclerosis and Central Nervous System Demyelinating Diseases Research and Therapeutics. “Such a diagnostic tool would be a great benefit to patients with MS and is consistent with the concepts of individualized medicine.”
Research Supports the Importance of Early Treatment in Patients With MS
Findings from two observational studies—CogniCIS and CogniMS—revealed that depression and fatigue occur alongside cognitive deficits, even early in the disease. Data from these studies showed that relatives were able to detect even minor changes in cognitive performance at an early stage of the disease, which the patients themselves did not report.
“Cognitive impairment in patients with multiple sclerosis (MS) is not sufficiently recognized, in spite of the significant negative impact it can have on patients’ lives,” said Dawn Langdon, PhD, Neuropsychology Lead and Reader in Neuropsychology, Royal Holloway, University of London, UK, and lead investigator of CogniCIS and CogniMS. “These studies will help us construct a more complete picture of the development and impact of cognitive decline in early MS. Such findings, added to the existing evidence, will have important implications for physicians when making management decisions.”
The CogniCIS study collected cognitive and psychosocial data from 394 patients with clinically isolated syndrome (CIS). A subset of 130 European patients with CIS and 60 of their relatives completed the MS Neuropsychological Questionnaire (MSNQ), which asks about cognitive difficulties. Preliminary results presented showed that scores on the MSNQ from patients with CIS and their relatives correlated more with the patients’ level of depression, fatigue, and quality of life rather than performance in cognitive tests.
The CogniMS study included psychosocial data from 1,509 patients with early MS. A subset of 274 patients and 178 of their relatives completed the MSNQ. According to preliminary findings from the trial, relatives’ reports of the patients’ cognition correlated with some cognitive test scores, obtained by patients; patient self-reported cognitive deficits were not closely related to objective test scores. Similar to results from CogniCIS, the CogniMS findings suggest that self-reported cognitive deficits in an early MS population are not specific to cognition, and are influenced by the patients’ psychologic situation.
25th Congress of the European Committee for Treatment and Research in MS (ECTRIMS), Dusseldorf, Germany
Fewer Injection Site Reactions Occur in Patients Using Interferon Beta-1a IM
Data from an observational phase IV study of 499 patients—the Swiss MS Skin Project—showed that patients with multiple sclerosis (MS) taking interferon beta-1a IM reported significantly fewer injection site reactions, compared with patients who took interferon beta-1b, glatiramer acetate, or interferon beta-1a. The study also found that patients taking interferon beta-1a IM were less likely to have missed a dose due to an injection site reaction in the four weeks prior to first assessment than those patients on other interferon therapies.
“This study showed that treatment with interferon beta-1a IM leads to fewer injection site reactions, which is an important factor in improving compliance,” said Karsten Beer, lead investigator for the study and a private neurologist in Wil, Switzerland. “As the only once-weekly injection treatment, interferon beta-1a IM offers people with relapsing MS an easy-to-use and highly effective treatment option. Convenience of an MS therapy is an important consideration for patients, as they do not want a therapy that will interfere with their daily lives.”
The Swiss MS Skin Project was designed to determine the frequency of injection site reactions, including skin necrosis and lipoatrophy, in patients taking interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a. Injection site reactions are believed to reduce treatment compliance among patients. The study enrolled nearly 500 patients on interferon beta-1a IM, interferon beta-1b, glatiramer acetate, or interferon beta-1a for a minimum of two years (mean treatment duration, 5.9 years) and followed patients for one year.
At the first assessment, significantly fewer patients who took interferon beta-1a IM experienced injection site reactions (13.4% vs 57.7% of those who used interferon beta-1b, 30.4% for glatiramer acetate, and 67.9% for interferon beta-1a); necrosis (0% vs 5.7% for interferon beta-1b, 0% for glatiramer acetate, and 6.0% for interferon beta-1a); and lipoatrophy (1.2 % vs 8.9% for interferon beta-1b, 13.0% for glatiramer acetate, and 10.3% for interferon beta-1a).
No patients who used interferon beta-1a IM missed a dose in the four weeks prior to first assessment due to injection site reactions (vs 5.7% of patients using interferon beta-1b, 4.3% for glatiramer acetate, and 7.1% for interferon beta-1a). These percentages were statistically significant, compared with use of interferon beta-1b and interferon beta-1a. In addition, significantly more patients remained on interferon beta-1a IM throughout the one-year trial (86.6% vs 79.7% of subjects who used interferon beta-1b, 60.9% for glatiramer acetate, and 83.2% for interferon beta-1a) than on any other treatment.
Patients Taking Natalizumab Report Improvement in Physical and Psychologic Well-Being
Patients with multiple sclerosis (MS) taking natalizumab experienced an improvement in both their physical function and psychologic well-being, according to six-month results of an ongoing, one-year longitudinal, observational, patient-reported outcomes study. The study, which was the first to assess patient experiences with natalizumab in usual-care settings, found that patients who used natalizumab reported an improvement in their overall quality of life.
“The symptoms that a patient with MS deals with on a daily basis result in significant psychologic and physical effects that can adversely impact their quality of life,” said William Stuart, MD, Medical Director of the Multiple Sclerosis Center of Atlanta. “In a previous pivotal trial, natalizumab not only showed a reduction in relapse rates and disability progression, but also improved quality of life. Results from this observational study further demonstrate the impact of natalizumab on improving MS patients’ well-being as reported by patients who live with this disease every day.”
The trial assessed health outcomes from patients’ perspectives before starting natalizumab and after the third, sixth, and 12th infusions of the drug. A majority of the patients in the study are female (76.3%), with a mean age of 46.6 and mean disease duration of 10 years.
After six natalizumab infusions, patients reported statistically significant improvement in disease-specific quality of life, measured with use of the MS Impact Scale-29 (MSIS-29), which assesses the physical impact of MS in terms of mobility and self-care, as well as the psychologic impact of MS in terms of anxiety/depression, with lower scores indicating better quality of life. Patients also reported statistically significant improvement in general health-related quality of life, as measured by the 12-item Short Form Scale (SF-12) health survey, which assesses the physical and mental health, with higher scores indicating better quality of life.
Both scales assess patient experience of the physical and psychologic aspects of quality of life. For the MSIS-29 subscales, statistically significant improvements were observed over time for both the physical (baseline, 46.87; third infusion, 39.60; sixth infusion, 39.27) and psychologic (baseline, 41.56; third infusion, 33.77; sixth infusion, 33.20) impact scores.
SF-12 physical component summary score (baseline, 34.20; third infusion, 36.05; sixth infusion, 36.34) and the SF-12 mental component summary score (baseline, 43.25; third infusion, 47.35; sixth infusion, 47.92) showed statistically significant improvements over time.
[Editor’s note: For more information on natalizumab, please see a related news story and commentary on page 5.]
Genetic Targets for Potential MS Therapies
Two genes in mice were associated with good CNS repair in multiple sclerosis (MS). The findings may help researchers develop more effective therapies and predict outcomes for patients with MS.
“Most MS genetic studies have looked at disease susceptibility—or why some people get MS and others do not,” said Allan Bieber, PhD, Assistant Professor of Neurology at the Mayo Clinic in Rochester, Minnesota. “This study asked, among those who have MS, why some do well with the disease while others do poorly, and what might be the genetic determinants of this difference in outcome.”
Dr. Bieber and a team of Mayo Clinic researchers used two different strains of mice with a chronic, progressive MS-like disease. One strain of mice progressed to paralysis and death. The other strain underwent the initial damage induction phase of the disease and then had spontaneous repair of the damage to the CNS and retained most neurologic function. Using the genetic mapping techniques that are available for mice, the team mapped two strong genetic determinants of good disease outcome.
“It’s possible that the identification of these genes may provide the first important clue as to why some patients with MS do well, while others do not,” said Dr. Bieber. “The genetic data indicate that good CNS repair results from stimulation of one genetic pathway and inhibition of another genetic pathway. While we’re still in the early stages of this research, it could eventually lead to the development of useful therapies that stimulate or inhibit these genetic pathways in patients with MS.”
According to Dr. Bieber, the research suggests that there may be a small number of strong genetic determinants for CNS repair following demyelinating disease, rather than a larger number of weak determinants.
“If that’s true, it may be possible to map the most important genetic determinants of CNS repair in patients with MS and define a reparative genotype that could predict patients’ outcomes,” said Moses Rodriguez, MD, Professor of Neurology and Director of the Mayo Clinic’s Center for Multiple Sclerosis and Central Nervous System Demyelinating Diseases Research and Therapeutics. “Such a diagnostic tool would be a great benefit to patients with MS and is consistent with the concepts of individualized medicine.”
Research Supports the Importance of Early Treatment in Patients With MS
Findings from two observational studies—CogniCIS and CogniMS—revealed that depression and fatigue occur alongside cognitive deficits, even early in the disease. Data from these studies showed that relatives were able to detect even minor changes in cognitive performance at an early stage of the disease, which the patients themselves did not report.
“Cognitive impairment in patients with multiple sclerosis (MS) is not sufficiently recognized, in spite of the significant negative impact it can have on patients’ lives,” said Dawn Langdon, PhD, Neuropsychology Lead and Reader in Neuropsychology, Royal Holloway, University of London, UK, and lead investigator of CogniCIS and CogniMS. “These studies will help us construct a more complete picture of the development and impact of cognitive decline in early MS. Such findings, added to the existing evidence, will have important implications for physicians when making management decisions.”
The CogniCIS study collected cognitive and psychosocial data from 394 patients with clinically isolated syndrome (CIS). A subset of 130 European patients with CIS and 60 of their relatives completed the MS Neuropsychological Questionnaire (MSNQ), which asks about cognitive difficulties. Preliminary results presented showed that scores on the MSNQ from patients with CIS and their relatives correlated more with the patients’ level of depression, fatigue, and quality of life rather than performance in cognitive tests.
The CogniMS study included psychosocial data from 1,509 patients with early MS. A subset of 274 patients and 178 of their relatives completed the MSNQ. According to preliminary findings from the trial, relatives’ reports of the patients’ cognition correlated with some cognitive test scores, obtained by patients; patient self-reported cognitive deficits were not closely related to objective test scores. Similar to results from CogniCIS, the CogniMS findings suggest that self-reported cognitive deficits in an early MS population are not specific to cognition, and are influenced by the patients’ psychologic situation.
New Guidelines for the Diagnosis and Follow-Up of MS Using MRI
Revised clinical practice guidelines for MRI in MS incorporate new information and practice recommendations that will help patients, physicians, and care providers, according to an international working group of MS researchers.
ATLANTA—Revised guidelines regarding an MRI protocol for the diagnosis and follow-up of multiple sclerosis (MS) were presented at the 2009 Annual Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). “The new guidelines incorporate new information and practice recommendations that will benefit patients and will be useful for physicians and care providers,” stated Anthony Traboulsee, MD, Assistant Professor of Neurology at the University of British Columbia, Vancouver, Canada, and a member of the working group of international neurologists and radiologists who devised the guidelines.
Standardized Protocol Recommendations
No specific recommendations were made for magnet size or strength, although scans should be of good quality, with adequate signal noise ratio and resolution. However, some of the lower field strength magnets or older machines will probably not be able to produce optimal images under these guidelines, noted Lael Stone, MD, Staff Neurologist at Cleveland Clinic’s Mellen Center, and member of the MS working group.
Core brain MRI sequences are listed as sagittal fluid attenuated inversion recovery (FLAIR); axial FLAIR; axial T2; and axial T1 pre- and post-gadolinium. Core spinal cord MRI sequences are listed as sagittal T2, sagittal proton density or short tau invasion recovery, and sagittal T1.
The guidelines also address the requisition, reporting, and storage of MRIs. Physicians should request the standardized brain and/or spinal cord protocol, indicate the clinical question being addressed, and make the radiologist and technologist aware of relevant medical history, physical findings, and MS medications, as well as the date and place of any previous MRIs. Radiologists should report the lesion number, location, size, shape, and character, as well as whether MRI criteria for dissemination in space and time are met. A comparison with previous studies for new lesion activity and atrophy should be performed whenever possible, assuming that the images are of comparable quality and acquisition. Copies of the MRI studies should be kept permanently, and digital media are the most sensible manner for archiving.
Clinical Indications
For patients with a clinically isolated syndrome (CIS) and suspected MS, the researchers recommend a brain MRI with and without a gadolinium contrast agent at baseline evaluation. They also recommend a spinal cord MRI if persisting uncertainty exists about the diagnosis and/or the findings on brain MRI are equivocal, and if presenting symptoms or signs are at the level of the spinal cord. During a follow-up examination, a brain MRI with and without a gadolinium contrast agent is advised to detect new disease activity.
In noting that an initial brain MRI is recommended when available, “We wanted to recognize that there are some areas of the world, and frankly also in the United States, where it’s very difficult to obtain an MRI for a variety of reasons,” said Dr. Stone.
Among patients with definite MS, the guidelines authors recommend a brain MRI with gadolinium at baseline evaluation and during follow-up. “To assess subclinical disease activity, [brain MRI with and without gadolinium contrast] should be considered every one to two years,” reported the authors. “The exact frequency may vary depending on clinical course and other clinical features.”
“You’ve heard over and over again that MS is a clinical diagnosis but with newer criteria,” commented Dr. Stone. “We are emphasizing the fact that clinically silent lesions on an MRI can count toward dissemination of time or space.”
Dr. Stone emphasized that the goal of setting an MRI frequency timeline was to recommend, not dictate. “We want to emphasize the fact that at least it should pass through one’s consciousness, as to the appropriateness,” she pointed out. “The exact frequency may vary depending on clinical course and other clinical features.” The reasons for follow-up with a brain MRI with and without gadolinium contrast—to evaluate an unexpected clinical worsening that causes concern for diagnosis, to reassess the original diagnosis, and to reassess before starting or modifying therapy—also support the new recommendation. “The threshold for defining a response on MRI that is clinically meaningful in the short term and long term, including the potential effects of newer quantitative techniques, is evolving,” Dr. Stone stated.”
Suggested Reading
Simon JH, Li D, Traboulsee A, et al. Standardized MR imaging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. AJNR Am J Neuroradiol. 2006;27(2):455-461.
Revised clinical practice guidelines for MRI in MS incorporate new information and practice recommendations that will help patients, physicians, and care providers, according to an international working group of MS researchers.
ATLANTA—Revised guidelines regarding an MRI protocol for the diagnosis and follow-up of multiple sclerosis (MS) were presented at the 2009 Annual Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). “The new guidelines incorporate new information and practice recommendations that will benefit patients and will be useful for physicians and care providers,” stated Anthony Traboulsee, MD, Assistant Professor of Neurology at the University of British Columbia, Vancouver, Canada, and a member of the working group of international neurologists and radiologists who devised the guidelines.
Standardized Protocol Recommendations
No specific recommendations were made for magnet size or strength, although scans should be of good quality, with adequate signal noise ratio and resolution. However, some of the lower field strength magnets or older machines will probably not be able to produce optimal images under these guidelines, noted Lael Stone, MD, Staff Neurologist at Cleveland Clinic’s Mellen Center, and member of the MS working group.
Core brain MRI sequences are listed as sagittal fluid attenuated inversion recovery (FLAIR); axial FLAIR; axial T2; and axial T1 pre- and post-gadolinium. Core spinal cord MRI sequences are listed as sagittal T2, sagittal proton density or short tau invasion recovery, and sagittal T1.
The guidelines also address the requisition, reporting, and storage of MRIs. Physicians should request the standardized brain and/or spinal cord protocol, indicate the clinical question being addressed, and make the radiologist and technologist aware of relevant medical history, physical findings, and MS medications, as well as the date and place of any previous MRIs. Radiologists should report the lesion number, location, size, shape, and character, as well as whether MRI criteria for dissemination in space and time are met. A comparison with previous studies for new lesion activity and atrophy should be performed whenever possible, assuming that the images are of comparable quality and acquisition. Copies of the MRI studies should be kept permanently, and digital media are the most sensible manner for archiving.
Clinical Indications
For patients with a clinically isolated syndrome (CIS) and suspected MS, the researchers recommend a brain MRI with and without a gadolinium contrast agent at baseline evaluation. They also recommend a spinal cord MRI if persisting uncertainty exists about the diagnosis and/or the findings on brain MRI are equivocal, and if presenting symptoms or signs are at the level of the spinal cord. During a follow-up examination, a brain MRI with and without a gadolinium contrast agent is advised to detect new disease activity.
In noting that an initial brain MRI is recommended when available, “We wanted to recognize that there are some areas of the world, and frankly also in the United States, where it’s very difficult to obtain an MRI for a variety of reasons,” said Dr. Stone.
Among patients with definite MS, the guidelines authors recommend a brain MRI with gadolinium at baseline evaluation and during follow-up. “To assess subclinical disease activity, [brain MRI with and without gadolinium contrast] should be considered every one to two years,” reported the authors. “The exact frequency may vary depending on clinical course and other clinical features.”
“You’ve heard over and over again that MS is a clinical diagnosis but with newer criteria,” commented Dr. Stone. “We are emphasizing the fact that clinically silent lesions on an MRI can count toward dissemination of time or space.”
Dr. Stone emphasized that the goal of setting an MRI frequency timeline was to recommend, not dictate. “We want to emphasize the fact that at least it should pass through one’s consciousness, as to the appropriateness,” she pointed out. “The exact frequency may vary depending on clinical course and other clinical features.” The reasons for follow-up with a brain MRI with and without gadolinium contrast—to evaluate an unexpected clinical worsening that causes concern for diagnosis, to reassess the original diagnosis, and to reassess before starting or modifying therapy—also support the new recommendation. “The threshold for defining a response on MRI that is clinically meaningful in the short term and long term, including the potential effects of newer quantitative techniques, is evolving,” Dr. Stone stated.”
Revised clinical practice guidelines for MRI in MS incorporate new information and practice recommendations that will help patients, physicians, and care providers, according to an international working group of MS researchers.
ATLANTA—Revised guidelines regarding an MRI protocol for the diagnosis and follow-up of multiple sclerosis (MS) were presented at the 2009 Annual Meeting of the Consortium of MS Centers (CMSC) and the Americas Committee for Treatment and Research in MS (ACTRIMS). “The new guidelines incorporate new information and practice recommendations that will benefit patients and will be useful for physicians and care providers,” stated Anthony Traboulsee, MD, Assistant Professor of Neurology at the University of British Columbia, Vancouver, Canada, and a member of the working group of international neurologists and radiologists who devised the guidelines.
Standardized Protocol Recommendations
No specific recommendations were made for magnet size or strength, although scans should be of good quality, with adequate signal noise ratio and resolution. However, some of the lower field strength magnets or older machines will probably not be able to produce optimal images under these guidelines, noted Lael Stone, MD, Staff Neurologist at Cleveland Clinic’s Mellen Center, and member of the MS working group.
Core brain MRI sequences are listed as sagittal fluid attenuated inversion recovery (FLAIR); axial FLAIR; axial T2; and axial T1 pre- and post-gadolinium. Core spinal cord MRI sequences are listed as sagittal T2, sagittal proton density or short tau invasion recovery, and sagittal T1.
The guidelines also address the requisition, reporting, and storage of MRIs. Physicians should request the standardized brain and/or spinal cord protocol, indicate the clinical question being addressed, and make the radiologist and technologist aware of relevant medical history, physical findings, and MS medications, as well as the date and place of any previous MRIs. Radiologists should report the lesion number, location, size, shape, and character, as well as whether MRI criteria for dissemination in space and time are met. A comparison with previous studies for new lesion activity and atrophy should be performed whenever possible, assuming that the images are of comparable quality and acquisition. Copies of the MRI studies should be kept permanently, and digital media are the most sensible manner for archiving.
Clinical Indications
For patients with a clinically isolated syndrome (CIS) and suspected MS, the researchers recommend a brain MRI with and without a gadolinium contrast agent at baseline evaluation. They also recommend a spinal cord MRI if persisting uncertainty exists about the diagnosis and/or the findings on brain MRI are equivocal, and if presenting symptoms or signs are at the level of the spinal cord. During a follow-up examination, a brain MRI with and without a gadolinium contrast agent is advised to detect new disease activity.
In noting that an initial brain MRI is recommended when available, “We wanted to recognize that there are some areas of the world, and frankly also in the United States, where it’s very difficult to obtain an MRI for a variety of reasons,” said Dr. Stone.
Among patients with definite MS, the guidelines authors recommend a brain MRI with gadolinium at baseline evaluation and during follow-up. “To assess subclinical disease activity, [brain MRI with and without gadolinium contrast] should be considered every one to two years,” reported the authors. “The exact frequency may vary depending on clinical course and other clinical features.”
“You’ve heard over and over again that MS is a clinical diagnosis but with newer criteria,” commented Dr. Stone. “We are emphasizing the fact that clinically silent lesions on an MRI can count toward dissemination of time or space.”
Dr. Stone emphasized that the goal of setting an MRI frequency timeline was to recommend, not dictate. “We want to emphasize the fact that at least it should pass through one’s consciousness, as to the appropriateness,” she pointed out. “The exact frequency may vary depending on clinical course and other clinical features.” The reasons for follow-up with a brain MRI with and without gadolinium contrast—to evaluate an unexpected clinical worsening that causes concern for diagnosis, to reassess the original diagnosis, and to reassess before starting or modifying therapy—also support the new recommendation. “The threshold for defining a response on MRI that is clinically meaningful in the short term and long term, including the potential effects of newer quantitative techniques, is evolving,” Dr. Stone stated.”
Suggested Reading
Simon JH, Li D, Traboulsee A, et al. Standardized MR imaging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. AJNR Am J Neuroradiol. 2006;27(2):455-461.
Suggested Reading
Simon JH, Li D, Traboulsee A, et al. Standardized MR imaging protocol for multiple sclerosis: Consortium of MS Centers consensus guidelines. AJNR Am J Neuroradiol. 2006;27(2):455-461.
Literature Monitor
Stroke After Cardiac Surgery and Role of Carotid Stenosis
Combining carotid and cardiac procedures is neither necessary nor effective in reducing postoperative stroke in patients with asymptomatic carotid stenosis, according to a study in the September Archives of Neurology. Researchers found no direct causal relationship between significant carotid stenosis and postoperative stroke in patients who underwent cardiac operations.
Yuebing Li, MD, PhD, and colleagues at Lehigh Valley Hospital and Health Network in Allentown, Pennsylvania, reviewed data of 4,335 patients receiving nonurgent coronary artery bypass grafting (CABG) and/or aortic valve replacement between July 2001 and December 2006. Prior to surgery, 3,942 patients were evaluated for carotid stenosis using high-resolution sonography, 239 (6.1%) of whom were identified as having significant carotid stenosis.
A total of 76 patients (1.8%) had a clinically definitive stroke following surgery. Of those, 18 patients had significant carotid stenosis (23.7%). Although stroke was more common in individuals with carotid stenosis than in those without (7.5% vs 1.8%), 14 of the 18 strokes “occurred outside the territory of diseased carotid artery,” the study authors noted. Furthermore, the majority (76.3%) of postoperative strokes occurred in individuals without carotid disease, and 60% of the strokes were not confined to a single carotid artery.
“According to clinical data, in 94.7% of patients, stroke occurred without direct correlation to significant carotid stenosis,” the study authors wrote. “This study strongly suggests there is no direct causal relationship between postoperative stroke and severe carotid stenosis.”
In a related editorial, Louis R. Caplan, MD, Professor of Neurology at Harvard Medical School in Boston, commented on the neurologic complications of elective coronary artery surgery. “Processes that include checklists and time-outs during which the team reviews findings and strategies have led to reduced medical errors and improved outcomes,” Dr. Caplan wrote. “I suggest that patients and preoperative information should be reviewed before surgery by a team approach that includes a cardiologist who will observe the patients throughout their hospitalization and the cardiac surgeon who will perform the operation.”
Li Y, Walicki D, Mathiesen C, et al. Strokes after cardiac surgery and relationship to carotid stenosis. Arch Neurol. 2009;66(9):1091-1096.
Caplan LR. Translating what is known about neurological complications of coronary artery bypass graft surgery into action. Arch Neurol. 2009;66(9):1062-1064.
CT Scans in Children With Head Injury
Researchers have identified guidelines for accurately predicting children at very low risk of clinically important traumatic brain injuries (TBI), for whom CT scans should be avoided, as reported in the September 15 online Lancet. Nathan Kuppermann, MD, of the University of California-Davis School of Medicine in Sacramento, and colleagues analyzed 42,412 children with head trauma in 25 North American emergency departments, and derived and validated age-specific prediction rules for clinically important TBI. Application of these rules, the investigators believe, could limit CT use, protecting children from unnecessary radiation risks.
Dr. Kuppermann’s group, the Pediatric Emergency Care Applied Research Network, identified the following algorithms with 100% and 99.95% negative predictive value for clinically important TBI, respectively:
• For children younger than 2, normal mental status, no scalp hematoma except frontal, no loss of consciousness or loss of consciousness for less than 5 seconds, nonsevere injury mechanism, no palpable skull fracture, and acting normally according to the parents.
• For children 2 and older, normal mental status, no loss of consciousness, no vomiting, nonsevere injury mechanism, no signs of basilar skull fracture, and no severe headache.
“Data to guide clinical decision making for children with head trauma are urgently needed because head trauma is common and CT use is increasing,” the study authors commented. “Children sustaining minor head trauma infrequently have TBI and rarely need neurosurgery. The small risk of clinically important TBI should be balanced against the risks of ionizing radiation of CTs.”
“Kuppermann and colleagues remind us that the rules are meant to inform clinical decision making, not to replace it,” Patricia C. Parkin, MD, and Jonathon L. Maguire, MD, of the Division of Pediatric Medicine and the Pediatric Outcomes Research Team at the Hospital for Sick Children in Toronto, wrote in an accompanying comment. “The next challenge for evidence-based medicine is knowledge translation. Decision aids might provide structured presentations of options and outcomes.”
Kuppermann N, Holmes JF, Dayan PS, et al. Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet. 2009 Sep 14; [Epub ahead of print].
Parkin PC, Maguire JL. Clinically important head injuries after head trauma in children. Lancet. 2009 Sep 14; [Epub ahead of print].
Parent-of-Origin Effects in MS
The greater female-to-male ratio in patients with multiple sclerosis (MS) appears to be more strongly related to the mother, a study published in the August 25 Neurology reported. This maternal parent-of-origin effect, previously seen in studies of half-siblings and avuncular pairs, was found in offspring from a Caucasian mother and North American Aboriginal father.
S.V. Ramagopalan, DPhil, of the Wellcome Trust Centre for Human Genetics at the University of Oxford, UK, and colleagues examined 30,000 MS cases from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) and identified 58 individuals with one Caucasian parent and one North American Aboriginal parent. Of these, 27 had a Caucasian mother and 31 had a North American Aboriginal mother. Although the total number of affected offspring was similar in the two mating types studied, the sex ratio differed. Female-to-male sex ratio was 7:1 for patients with MS who had a Caucasian mother, compared with a 2:1 ratio for those with a Caucasian father.
“A parent-of-origin effect (maternal) has been repeatedly observed in MS, based on studies of half-siblings, sibships including dizygotic twins, a large extended Dutch pedigree, and avuncular pairs, as well as timing of birth effect,” the study authors noted. “The comparison of offspring from interracial matings is a novel method of analysis to look for parent of origin effects.
“The data from this study hint at an intriguing possibility that the observed female preponderance of MS could result from environmental factors acting upon mothers to differentially affect MS risk more in female than in male offspring,” the researchers pointed out.
In a related editorial, John W. Rose, MD, commented that this study “illustrated the continued potential of the CCPGSMS to address interesting questions related to the disease.… By evaluating a small set of MS patients with a Caucasian parent and a Native Aboriginal American parent, the investigators were able to assess parental effects on the disease,” he continued. “The susceptibility to disease is presumed to be predominantly introduced by the Caucasian parent based on previous investigations. In this admixture study, the results demonstrate a maternal effect which strongly influences the sex ratio of offspring affected by MS, linking these two classes of gender differences in MS.”
Ramagopalan SV, Yee IM, Dyment DA, et al. Parent-of-origin effect in multiple sclerosis: observations from interracial matings. Neurology. 2009;73(8):602-605.
Rose JW. Multiple sclerosis: evidence of maternal effects and an increasing incidence in women. Neurology. 2009;73(8):578-579.
Stroke After Cardiac Surgery and Role of Carotid Stenosis
Combining carotid and cardiac procedures is neither necessary nor effective in reducing postoperative stroke in patients with asymptomatic carotid stenosis, according to a study in the September Archives of Neurology. Researchers found no direct causal relationship between significant carotid stenosis and postoperative stroke in patients who underwent cardiac operations.
Yuebing Li, MD, PhD, and colleagues at Lehigh Valley Hospital and Health Network in Allentown, Pennsylvania, reviewed data of 4,335 patients receiving nonurgent coronary artery bypass grafting (CABG) and/or aortic valve replacement between July 2001 and December 2006. Prior to surgery, 3,942 patients were evaluated for carotid stenosis using high-resolution sonography, 239 (6.1%) of whom were identified as having significant carotid stenosis.
A total of 76 patients (1.8%) had a clinically definitive stroke following surgery. Of those, 18 patients had significant carotid stenosis (23.7%). Although stroke was more common in individuals with carotid stenosis than in those without (7.5% vs 1.8%), 14 of the 18 strokes “occurred outside the territory of diseased carotid artery,” the study authors noted. Furthermore, the majority (76.3%) of postoperative strokes occurred in individuals without carotid disease, and 60% of the strokes were not confined to a single carotid artery.
“According to clinical data, in 94.7% of patients, stroke occurred without direct correlation to significant carotid stenosis,” the study authors wrote. “This study strongly suggests there is no direct causal relationship between postoperative stroke and severe carotid stenosis.”
In a related editorial, Louis R. Caplan, MD, Professor of Neurology at Harvard Medical School in Boston, commented on the neurologic complications of elective coronary artery surgery. “Processes that include checklists and time-outs during which the team reviews findings and strategies have led to reduced medical errors and improved outcomes,” Dr. Caplan wrote. “I suggest that patients and preoperative information should be reviewed before surgery by a team approach that includes a cardiologist who will observe the patients throughout their hospitalization and the cardiac surgeon who will perform the operation.”
Li Y, Walicki D, Mathiesen C, et al. Strokes after cardiac surgery and relationship to carotid stenosis. Arch Neurol. 2009;66(9):1091-1096.
Caplan LR. Translating what is known about neurological complications of coronary artery bypass graft surgery into action. Arch Neurol. 2009;66(9):1062-1064.
CT Scans in Children With Head Injury
Researchers have identified guidelines for accurately predicting children at very low risk of clinically important traumatic brain injuries (TBI), for whom CT scans should be avoided, as reported in the September 15 online Lancet. Nathan Kuppermann, MD, of the University of California-Davis School of Medicine in Sacramento, and colleagues analyzed 42,412 children with head trauma in 25 North American emergency departments, and derived and validated age-specific prediction rules for clinically important TBI. Application of these rules, the investigators believe, could limit CT use, protecting children from unnecessary radiation risks.
Dr. Kuppermann’s group, the Pediatric Emergency Care Applied Research Network, identified the following algorithms with 100% and 99.95% negative predictive value for clinically important TBI, respectively:
• For children younger than 2, normal mental status, no scalp hematoma except frontal, no loss of consciousness or loss of consciousness for less than 5 seconds, nonsevere injury mechanism, no palpable skull fracture, and acting normally according to the parents.
• For children 2 and older, normal mental status, no loss of consciousness, no vomiting, nonsevere injury mechanism, no signs of basilar skull fracture, and no severe headache.
“Data to guide clinical decision making for children with head trauma are urgently needed because head trauma is common and CT use is increasing,” the study authors commented. “Children sustaining minor head trauma infrequently have TBI and rarely need neurosurgery. The small risk of clinically important TBI should be balanced against the risks of ionizing radiation of CTs.”
“Kuppermann and colleagues remind us that the rules are meant to inform clinical decision making, not to replace it,” Patricia C. Parkin, MD, and Jonathon L. Maguire, MD, of the Division of Pediatric Medicine and the Pediatric Outcomes Research Team at the Hospital for Sick Children in Toronto, wrote in an accompanying comment. “The next challenge for evidence-based medicine is knowledge translation. Decision aids might provide structured presentations of options and outcomes.”
Kuppermann N, Holmes JF, Dayan PS, et al. Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet. 2009 Sep 14; [Epub ahead of print].
Parkin PC, Maguire JL. Clinically important head injuries after head trauma in children. Lancet. 2009 Sep 14; [Epub ahead of print].
Parent-of-Origin Effects in MS
The greater female-to-male ratio in patients with multiple sclerosis (MS) appears to be more strongly related to the mother, a study published in the August 25 Neurology reported. This maternal parent-of-origin effect, previously seen in studies of half-siblings and avuncular pairs, was found in offspring from a Caucasian mother and North American Aboriginal father.
S.V. Ramagopalan, DPhil, of the Wellcome Trust Centre for Human Genetics at the University of Oxford, UK, and colleagues examined 30,000 MS cases from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) and identified 58 individuals with one Caucasian parent and one North American Aboriginal parent. Of these, 27 had a Caucasian mother and 31 had a North American Aboriginal mother. Although the total number of affected offspring was similar in the two mating types studied, the sex ratio differed. Female-to-male sex ratio was 7:1 for patients with MS who had a Caucasian mother, compared with a 2:1 ratio for those with a Caucasian father.
“A parent-of-origin effect (maternal) has been repeatedly observed in MS, based on studies of half-siblings, sibships including dizygotic twins, a large extended Dutch pedigree, and avuncular pairs, as well as timing of birth effect,” the study authors noted. “The comparison of offspring from interracial matings is a novel method of analysis to look for parent of origin effects.
“The data from this study hint at an intriguing possibility that the observed female preponderance of MS could result from environmental factors acting upon mothers to differentially affect MS risk more in female than in male offspring,” the researchers pointed out.
In a related editorial, John W. Rose, MD, commented that this study “illustrated the continued potential of the CCPGSMS to address interesting questions related to the disease.… By evaluating a small set of MS patients with a Caucasian parent and a Native Aboriginal American parent, the investigators were able to assess parental effects on the disease,” he continued. “The susceptibility to disease is presumed to be predominantly introduced by the Caucasian parent based on previous investigations. In this admixture study, the results demonstrate a maternal effect which strongly influences the sex ratio of offspring affected by MS, linking these two classes of gender differences in MS.”
Ramagopalan SV, Yee IM, Dyment DA, et al. Parent-of-origin effect in multiple sclerosis: observations from interracial matings. Neurology. 2009;73(8):602-605.
Rose JW. Multiple sclerosis: evidence of maternal effects and an increasing incidence in women. Neurology. 2009;73(8):578-579.
Stroke After Cardiac Surgery and Role of Carotid Stenosis
Combining carotid and cardiac procedures is neither necessary nor effective in reducing postoperative stroke in patients with asymptomatic carotid stenosis, according to a study in the September Archives of Neurology. Researchers found no direct causal relationship between significant carotid stenosis and postoperative stroke in patients who underwent cardiac operations.
Yuebing Li, MD, PhD, and colleagues at Lehigh Valley Hospital and Health Network in Allentown, Pennsylvania, reviewed data of 4,335 patients receiving nonurgent coronary artery bypass grafting (CABG) and/or aortic valve replacement between July 2001 and December 2006. Prior to surgery, 3,942 patients were evaluated for carotid stenosis using high-resolution sonography, 239 (6.1%) of whom were identified as having significant carotid stenosis.
A total of 76 patients (1.8%) had a clinically definitive stroke following surgery. Of those, 18 patients had significant carotid stenosis (23.7%). Although stroke was more common in individuals with carotid stenosis than in those without (7.5% vs 1.8%), 14 of the 18 strokes “occurred outside the territory of diseased carotid artery,” the study authors noted. Furthermore, the majority (76.3%) of postoperative strokes occurred in individuals without carotid disease, and 60% of the strokes were not confined to a single carotid artery.
“According to clinical data, in 94.7% of patients, stroke occurred without direct correlation to significant carotid stenosis,” the study authors wrote. “This study strongly suggests there is no direct causal relationship between postoperative stroke and severe carotid stenosis.”
In a related editorial, Louis R. Caplan, MD, Professor of Neurology at Harvard Medical School in Boston, commented on the neurologic complications of elective coronary artery surgery. “Processes that include checklists and time-outs during which the team reviews findings and strategies have led to reduced medical errors and improved outcomes,” Dr. Caplan wrote. “I suggest that patients and preoperative information should be reviewed before surgery by a team approach that includes a cardiologist who will observe the patients throughout their hospitalization and the cardiac surgeon who will perform the operation.”
Li Y, Walicki D, Mathiesen C, et al. Strokes after cardiac surgery and relationship to carotid stenosis. Arch Neurol. 2009;66(9):1091-1096.
Caplan LR. Translating what is known about neurological complications of coronary artery bypass graft surgery into action. Arch Neurol. 2009;66(9):1062-1064.
CT Scans in Children With Head Injury
Researchers have identified guidelines for accurately predicting children at very low risk of clinically important traumatic brain injuries (TBI), for whom CT scans should be avoided, as reported in the September 15 online Lancet. Nathan Kuppermann, MD, of the University of California-Davis School of Medicine in Sacramento, and colleagues analyzed 42,412 children with head trauma in 25 North American emergency departments, and derived and validated age-specific prediction rules for clinically important TBI. Application of these rules, the investigators believe, could limit CT use, protecting children from unnecessary radiation risks.
Dr. Kuppermann’s group, the Pediatric Emergency Care Applied Research Network, identified the following algorithms with 100% and 99.95% negative predictive value for clinically important TBI, respectively:
• For children younger than 2, normal mental status, no scalp hematoma except frontal, no loss of consciousness or loss of consciousness for less than 5 seconds, nonsevere injury mechanism, no palpable skull fracture, and acting normally according to the parents.
• For children 2 and older, normal mental status, no loss of consciousness, no vomiting, nonsevere injury mechanism, no signs of basilar skull fracture, and no severe headache.
“Data to guide clinical decision making for children with head trauma are urgently needed because head trauma is common and CT use is increasing,” the study authors commented. “Children sustaining minor head trauma infrequently have TBI and rarely need neurosurgery. The small risk of clinically important TBI should be balanced against the risks of ionizing radiation of CTs.”
“Kuppermann and colleagues remind us that the rules are meant to inform clinical decision making, not to replace it,” Patricia C. Parkin, MD, and Jonathon L. Maguire, MD, of the Division of Pediatric Medicine and the Pediatric Outcomes Research Team at the Hospital for Sick Children in Toronto, wrote in an accompanying comment. “The next challenge for evidence-based medicine is knowledge translation. Decision aids might provide structured presentations of options and outcomes.”
Kuppermann N, Holmes JF, Dayan PS, et al. Identification of children at very low risk of clinically-important brain injuries after head trauma: a prospective cohort study. Lancet. 2009 Sep 14; [Epub ahead of print].
Parkin PC, Maguire JL. Clinically important head injuries after head trauma in children. Lancet. 2009 Sep 14; [Epub ahead of print].
Parent-of-Origin Effects in MS
The greater female-to-male ratio in patients with multiple sclerosis (MS) appears to be more strongly related to the mother, a study published in the August 25 Neurology reported. This maternal parent-of-origin effect, previously seen in studies of half-siblings and avuncular pairs, was found in offspring from a Caucasian mother and North American Aboriginal father.
S.V. Ramagopalan, DPhil, of the Wellcome Trust Centre for Human Genetics at the University of Oxford, UK, and colleagues examined 30,000 MS cases from the Canadian Collaborative Project on Genetic Susceptibility to Multiple Sclerosis (CCPGSMS) and identified 58 individuals with one Caucasian parent and one North American Aboriginal parent. Of these, 27 had a Caucasian mother and 31 had a North American Aboriginal mother. Although the total number of affected offspring was similar in the two mating types studied, the sex ratio differed. Female-to-male sex ratio was 7:1 for patients with MS who had a Caucasian mother, compared with a 2:1 ratio for those with a Caucasian father.
“A parent-of-origin effect (maternal) has been repeatedly observed in MS, based on studies of half-siblings, sibships including dizygotic twins, a large extended Dutch pedigree, and avuncular pairs, as well as timing of birth effect,” the study authors noted. “The comparison of offspring from interracial matings is a novel method of analysis to look for parent of origin effects.
“The data from this study hint at an intriguing possibility that the observed female preponderance of MS could result from environmental factors acting upon mothers to differentially affect MS risk more in female than in male offspring,” the researchers pointed out.
In a related editorial, John W. Rose, MD, commented that this study “illustrated the continued potential of the CCPGSMS to address interesting questions related to the disease.… By evaluating a small set of MS patients with a Caucasian parent and a Native Aboriginal American parent, the investigators were able to assess parental effects on the disease,” he continued. “The susceptibility to disease is presumed to be predominantly introduced by the Caucasian parent based on previous investigations. In this admixture study, the results demonstrate a maternal effect which strongly influences the sex ratio of offspring affected by MS, linking these two classes of gender differences in MS.”
Ramagopalan SV, Yee IM, Dyment DA, et al. Parent-of-origin effect in multiple sclerosis: observations from interracial matings. Neurology. 2009;73(8):602-605.
Rose JW. Multiple sclerosis: evidence of maternal effects and an increasing incidence in women. Neurology. 2009;73(8):578-579.
Commentary: Natalizumab and MS—Where Do We Stand?
—Alina Rabinovich, MD, MS Fellow, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark
Multiple sclerosis (MS) is an autoimmune condition in which autoreactive T cells cross the blood-brain barrier and attack the CNS, causing demyelination and axonal damage. Natalizumab, the newest medication approved for relapsing-remitting MS, is a humanized monoclonal antibody that binds to alpha-4 integrin molecule and prevents T and B cells from entering the brain, thereby decreasing inflammation and thus CNS damage. It has shown great promise in two large-scale multicenter trials with proven effectiveness in decreasing disease relapse rate, as well as accumulation of disability. In general, natalizumab has been well tolerated. Liver abnormalities, allergic reactions, and fatigue are some of its mild side-effects. However, occurrence of progressive multifocal leukoencephalopathy (PML) among patients using natalizumab as part of combination treatment or as monotherapy has caused considerable apprehension among patients and health care professionals about its safety.
PML is a devastating but rare opportunistic viral infection, caused by the JC virus, seen most commonly in patients with HIV, leukemia, and organ transplantation. A novel presentation of PML in MS emerged as a result of natalizumab. Some of the proposed mechanisms are compromised brain immunosurveillance versus mobilization of bone marrow cells carrying the JC virus. Due to surfacing of this infection, natalizumab was taken off the market in 2005. However, careful risk-benefit analysis and studies showing a much greater health gain over the risk of developing PML allowed the drug to be reapproved by the FDA in 2006. Proper use is mandated, such that it is used primarily as a second-line agent in patients with relapsing forms of MS, close clinical surveillance of patients is maintained, and it remains a monotherapy only, as using it in combination with other immunosuppressive agents may greatly increase chances of opportunistic infections, especially PML.
To date, 14 cases of PML have been reported, with the last two published in the New England Journal of Medicine in September. All cases occurred after 12 or more months of treatment, and the majority of cases occurred after 14 months. It appears that natalizumab is very safe for the first year, with the risk of developing PML increasing thereafter. The overall risk of PML after the first 12-month period of treatment with natalizumab appears to be approximately one in 2,000 to 3,000, given the limited information we have available to date. The key is to use natalizumab correctly and with appropriate surveillance. Close patient observation and clinical vigilance are necessary for early detection of PML. As the diagnosis is made early, the drug discontinued and residual drug removed by plasmapheresis, some patients have done well despite the potential deleterious effects of immune reconstitution syndrome on the brain as the virus is eliminated. Patients must be informed that individual susceptibility is not known, and regular laboratory surveillance of the JC virus in the blood and urine is of limited use with current techniques. Therefore, clear risk assessment is difficult at this time. Each patient must be clearly informed of the symptoms of PML. In the future, ongoing analysis will clarify the true safety profile of natalizumab and better define its role in the treatment of MS.
—Alina Rabinovich, MD, MS Fellow, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark
Multiple sclerosis (MS) is an autoimmune condition in which autoreactive T cells cross the blood-brain barrier and attack the CNS, causing demyelination and axonal damage. Natalizumab, the newest medication approved for relapsing-remitting MS, is a humanized monoclonal antibody that binds to alpha-4 integrin molecule and prevents T and B cells from entering the brain, thereby decreasing inflammation and thus CNS damage. It has shown great promise in two large-scale multicenter trials with proven effectiveness in decreasing disease relapse rate, as well as accumulation of disability. In general, natalizumab has been well tolerated. Liver abnormalities, allergic reactions, and fatigue are some of its mild side-effects. However, occurrence of progressive multifocal leukoencephalopathy (PML) among patients using natalizumab as part of combination treatment or as monotherapy has caused considerable apprehension among patients and health care professionals about its safety.
PML is a devastating but rare opportunistic viral infection, caused by the JC virus, seen most commonly in patients with HIV, leukemia, and organ transplantation. A novel presentation of PML in MS emerged as a result of natalizumab. Some of the proposed mechanisms are compromised brain immunosurveillance versus mobilization of bone marrow cells carrying the JC virus. Due to surfacing of this infection, natalizumab was taken off the market in 2005. However, careful risk-benefit analysis and studies showing a much greater health gain over the risk of developing PML allowed the drug to be reapproved by the FDA in 2006. Proper use is mandated, such that it is used primarily as a second-line agent in patients with relapsing forms of MS, close clinical surveillance of patients is maintained, and it remains a monotherapy only, as using it in combination with other immunosuppressive agents may greatly increase chances of opportunistic infections, especially PML.
To date, 14 cases of PML have been reported, with the last two published in the New England Journal of Medicine in September. All cases occurred after 12 or more months of treatment, and the majority of cases occurred after 14 months. It appears that natalizumab is very safe for the first year, with the risk of developing PML increasing thereafter. The overall risk of PML after the first 12-month period of treatment with natalizumab appears to be approximately one in 2,000 to 3,000, given the limited information we have available to date. The key is to use natalizumab correctly and with appropriate surveillance. Close patient observation and clinical vigilance are necessary for early detection of PML. As the diagnosis is made early, the drug discontinued and residual drug removed by plasmapheresis, some patients have done well despite the potential deleterious effects of immune reconstitution syndrome on the brain as the virus is eliminated. Patients must be informed that individual susceptibility is not known, and regular laboratory surveillance of the JC virus in the blood and urine is of limited use with current techniques. Therefore, clear risk assessment is difficult at this time. Each patient must be clearly informed of the symptoms of PML. In the future, ongoing analysis will clarify the true safety profile of natalizumab and better define its role in the treatment of MS.
—Alina Rabinovich, MD, MS Fellow, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark
Multiple sclerosis (MS) is an autoimmune condition in which autoreactive T cells cross the blood-brain barrier and attack the CNS, causing demyelination and axonal damage. Natalizumab, the newest medication approved for relapsing-remitting MS, is a humanized monoclonal antibody that binds to alpha-4 integrin molecule and prevents T and B cells from entering the brain, thereby decreasing inflammation and thus CNS damage. It has shown great promise in two large-scale multicenter trials with proven effectiveness in decreasing disease relapse rate, as well as accumulation of disability. In general, natalizumab has been well tolerated. Liver abnormalities, allergic reactions, and fatigue are some of its mild side-effects. However, occurrence of progressive multifocal leukoencephalopathy (PML) among patients using natalizumab as part of combination treatment or as monotherapy has caused considerable apprehension among patients and health care professionals about its safety.
PML is a devastating but rare opportunistic viral infection, caused by the JC virus, seen most commonly in patients with HIV, leukemia, and organ transplantation. A novel presentation of PML in MS emerged as a result of natalizumab. Some of the proposed mechanisms are compromised brain immunosurveillance versus mobilization of bone marrow cells carrying the JC virus. Due to surfacing of this infection, natalizumab was taken off the market in 2005. However, careful risk-benefit analysis and studies showing a much greater health gain over the risk of developing PML allowed the drug to be reapproved by the FDA in 2006. Proper use is mandated, such that it is used primarily as a second-line agent in patients with relapsing forms of MS, close clinical surveillance of patients is maintained, and it remains a monotherapy only, as using it in combination with other immunosuppressive agents may greatly increase chances of opportunistic infections, especially PML.
To date, 14 cases of PML have been reported, with the last two published in the New England Journal of Medicine in September. All cases occurred after 12 or more months of treatment, and the majority of cases occurred after 14 months. It appears that natalizumab is very safe for the first year, with the risk of developing PML increasing thereafter. The overall risk of PML after the first 12-month period of treatment with natalizumab appears to be approximately one in 2,000 to 3,000, given the limited information we have available to date. The key is to use natalizumab correctly and with appropriate surveillance. Close patient observation and clinical vigilance are necessary for early detection of PML. As the diagnosis is made early, the drug discontinued and residual drug removed by plasmapheresis, some patients have done well despite the potential deleterious effects of immune reconstitution syndrome on the brain as the virus is eliminated. Patients must be informed that individual susceptibility is not known, and regular laboratory surveillance of the JC virus in the blood and urine is of limited use with current techniques. Therefore, clear risk assessment is difficult at this time. Each patient must be clearly informed of the symptoms of PML. In the future, ongoing analysis will clarify the true safety profile of natalizumab and better define its role in the treatment of MS.
Natalizumab and MS—Where Do We Stand?
Subclinical reactivation of a virus that causes progressive multifocal leukoencephalopathy (PML) occurs frequently in patients with multiple sclerosis (MS) who use natalizumab, according to a study in the September 10 issue of theNew England Journal of Medicine. In 2005, the drug was briefly taken off the market due to a potential link with PML and was reinstated in 2006 after further testing.
PML is induced by the JC virus, a typically dormant virus that is present in urine, but not blood, samples of about one-third of healthy adults. In immune compromised patients, such as those with leukemia or AIDS, the virus can cross into the bloodstream and travel to the brain, causing PML.
Asymptomatic Reactivation of the JC Virus Is Observed
Igor Koralnik, MD, of the Department of Neurology and Division of Viral Pathogenesis at Beth Israel Deaconess Medical Center, and Associate Professor of Neurology at Harvard Medical School in Boston, and colleagues included 19 patients (15 women; median age, 42; median disease duration, five years) who were treated with natalizumab at the MS Clinic of Beth Israel Deaconess Medical Center Neurology Department in Boston. Urine and blood samples were collected and tested for the JC virus at the start of treatment and again at three, six, 12, and 18 months.
At study onset, three of 16 patients’ urine samples tested positive for the JC virus, and all blood samples were negative. At 12 months, 12 of 19 (63%) patients tested positive in urine samples, and one tested positive in blood samples. At the end of the study, researchers found evidence of the JC virus in three of 15 plasma samples (20%) and in nine of 15 samples of peripheral-blood mononuclear cells (60%). In addition, no patients had a neurologic deficit or new brain lesions consistent with PML during the study.
Thorough Monitoring Is Recommended
“The frequency of JC viremia reached in our patients with MS who were treated with natalizumab was higher than that observed in patients infected with HIV and similar only to that seen in patients with PML,” Dr. Koralnik and colleagues reported. “Viremia followed the increase in viruria. Therefore, the initial site of JC virus reactivation may have been the kidney, owing perhaps to decreased immunosurveillance in this compartment caused by natalizumab, which led to a secondary spread of virus to hematopoietic sites and to the subsequent release of JC virus-infected cells into the bloodstream.
“Our findings suggest that monitoring for JC virus in the urine of patients receiving natalizumab therapy and also, after 18 months, in peripheral-blood mononuclear cells in patients with viruria could provide some insight into viral replication,” the study authors commented.
“It is possible that natalizumab has a direct negative effect on JC virus–specific T cells occurring at around one year of treatment, which may have participated in JC virus reactivation in the kidney and its subsequent spread into the blood,” Dr. Chen’s group concluded.
—Rebecca K. Abma
Suggested Reading
Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab.N Engl J Med. 2009;361(11):1067-1074.
Subclinical reactivation of a virus that causes progressive multifocal leukoencephalopathy (PML) occurs frequently in patients with multiple sclerosis (MS) who use natalizumab, according to a study in the September 10 issue of theNew England Journal of Medicine. In 2005, the drug was briefly taken off the market due to a potential link with PML and was reinstated in 2006 after further testing.
PML is induced by the JC virus, a typically dormant virus that is present in urine, but not blood, samples of about one-third of healthy adults. In immune compromised patients, such as those with leukemia or AIDS, the virus can cross into the bloodstream and travel to the brain, causing PML.
Asymptomatic Reactivation of the JC Virus Is Observed
Igor Koralnik, MD, of the Department of Neurology and Division of Viral Pathogenesis at Beth Israel Deaconess Medical Center, and Associate Professor of Neurology at Harvard Medical School in Boston, and colleagues included 19 patients (15 women; median age, 42; median disease duration, five years) who were treated with natalizumab at the MS Clinic of Beth Israel Deaconess Medical Center Neurology Department in Boston. Urine and blood samples were collected and tested for the JC virus at the start of treatment and again at three, six, 12, and 18 months.
At study onset, three of 16 patients’ urine samples tested positive for the JC virus, and all blood samples were negative. At 12 months, 12 of 19 (63%) patients tested positive in urine samples, and one tested positive in blood samples. At the end of the study, researchers found evidence of the JC virus in three of 15 plasma samples (20%) and in nine of 15 samples of peripheral-blood mononuclear cells (60%). In addition, no patients had a neurologic deficit or new brain lesions consistent with PML during the study.
Thorough Monitoring Is Recommended
“The frequency of JC viremia reached in our patients with MS who were treated with natalizumab was higher than that observed in patients infected with HIV and similar only to that seen in patients with PML,” Dr. Koralnik and colleagues reported. “Viremia followed the increase in viruria. Therefore, the initial site of JC virus reactivation may have been the kidney, owing perhaps to decreased immunosurveillance in this compartment caused by natalizumab, which led to a secondary spread of virus to hematopoietic sites and to the subsequent release of JC virus-infected cells into the bloodstream.
“Our findings suggest that monitoring for JC virus in the urine of patients receiving natalizumab therapy and also, after 18 months, in peripheral-blood mononuclear cells in patients with viruria could provide some insight into viral replication,” the study authors commented.
“It is possible that natalizumab has a direct negative effect on JC virus–specific T cells occurring at around one year of treatment, which may have participated in JC virus reactivation in the kidney and its subsequent spread into the blood,” Dr. Chen’s group concluded.
—Rebecca K. Abma
Subclinical reactivation of a virus that causes progressive multifocal leukoencephalopathy (PML) occurs frequently in patients with multiple sclerosis (MS) who use natalizumab, according to a study in the September 10 issue of theNew England Journal of Medicine. In 2005, the drug was briefly taken off the market due to a potential link with PML and was reinstated in 2006 after further testing.
PML is induced by the JC virus, a typically dormant virus that is present in urine, but not blood, samples of about one-third of healthy adults. In immune compromised patients, such as those with leukemia or AIDS, the virus can cross into the bloodstream and travel to the brain, causing PML.
Asymptomatic Reactivation of the JC Virus Is Observed
Igor Koralnik, MD, of the Department of Neurology and Division of Viral Pathogenesis at Beth Israel Deaconess Medical Center, and Associate Professor of Neurology at Harvard Medical School in Boston, and colleagues included 19 patients (15 women; median age, 42; median disease duration, five years) who were treated with natalizumab at the MS Clinic of Beth Israel Deaconess Medical Center Neurology Department in Boston. Urine and blood samples were collected and tested for the JC virus at the start of treatment and again at three, six, 12, and 18 months.
At study onset, three of 16 patients’ urine samples tested positive for the JC virus, and all blood samples were negative. At 12 months, 12 of 19 (63%) patients tested positive in urine samples, and one tested positive in blood samples. At the end of the study, researchers found evidence of the JC virus in three of 15 plasma samples (20%) and in nine of 15 samples of peripheral-blood mononuclear cells (60%). In addition, no patients had a neurologic deficit or new brain lesions consistent with PML during the study.
Thorough Monitoring Is Recommended
“The frequency of JC viremia reached in our patients with MS who were treated with natalizumab was higher than that observed in patients infected with HIV and similar only to that seen in patients with PML,” Dr. Koralnik and colleagues reported. “Viremia followed the increase in viruria. Therefore, the initial site of JC virus reactivation may have been the kidney, owing perhaps to decreased immunosurveillance in this compartment caused by natalizumab, which led to a secondary spread of virus to hematopoietic sites and to the subsequent release of JC virus-infected cells into the bloodstream.
“Our findings suggest that monitoring for JC virus in the urine of patients receiving natalizumab therapy and also, after 18 months, in peripheral-blood mononuclear cells in patients with viruria could provide some insight into viral replication,” the study authors commented.
“It is possible that natalizumab has a direct negative effect on JC virus–specific T cells occurring at around one year of treatment, which may have participated in JC virus reactivation in the kidney and its subsequent spread into the blood,” Dr. Chen’s group concluded.
—Rebecca K. Abma
Suggested Reading
Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab.N Engl J Med. 2009;361(11):1067-1074.
Suggested Reading
Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab.N Engl J Med. 2009;361(11):1067-1074.
News Roundup: New and Noteworthy Information
Higher diastolic blood pressure (DBP) is cross-sectionally and independently associated with cognitive impairment, investigators reported in the August 25 Neurology. The association was found after adjusting for economic factors, depressive symptoms, and current use of any antihyperintensive medication in 30,228 black and white men and women (45 and older). “An increment of 10 mm Hg in DBP was associated with a 7% higher odds of cognitive impairment,” the researchers stated. “No independent association was identified between impaired cognitive status and systolic blood pressure (odds ratio [OR], 1.02) or pulse pressure (OR, 0.99).” No evidence of nonlinear relationships between any blood pressure components and impaired cognitive status was found.
Use of smokeless tobacco products is associated with risk of fatal myocardial infarction and stroke, according to the August 18 online BMJ. Investigators from Sweden and the United States conducted a meta-analysis of 11 observational studies (primarily including men). “Eight risk estimates were available for fatal myocardial infarction: the relative risk for ever use of smokeless tobacco products was 1.13 and the excess risk was restricted to current users,” the investigators stated. “The relative risk of fatal stroke, on the basis of five risk estimates, was 1.40.” Increased risk of fatal myocardial infarction was shown in studies from both geographic locations. “Data on dose-response were limited but did not suggest a strong relation between risk of dying from either disease and frequency or duration of use of smokeless tobacco products,” the researchers noted.
A mutation in transcriptional repressor hDEC2-P385R is associated with a human short sleep phenotype, according to a study in the August 14 issue of Science. Investigators found that within a small extended family, two members with the mutation had lifelong shorter daily sleep requirements than most persons. The researchers then genetically engineered mice and fruit flies to express the mutated human gene and studied its impact on behavior and sleep patterns. “Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time- and sleep deprivation-dependent manner,” the study authors stated. “These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.”
The FDA has approved Extavia for reducing the frequency of clinical exacerbations in patients with relapsing forms of multiple sclerosis (MS). It is also indicated in patients who have had a first clinical episode of MS and have features consistent with the disease as shown by MRI. Extavia is a new branded version of interferon beta-1b and the same medicinal product as Betaseron. Interferon beta-1b has been shown to reduce annualized relapse rates by 34%, with patients nearly twice as likely to remain relapse-free for more than two years, compared with those receiving placebo. Injection site necrosis has been reported in 4% of patients in controlled trials, and anaphylaxis has been reported as a rare complication of interferon use. Extavia is marketed by the Pharmaceuticals Division of Novartis (East Hanover, NJ) and is expected to be available this fall.
White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (aMCI), and infarcts are more strongly related to nonamnestic MCI, according to a study in the August 11 issue of Neurology. Researchers investigated the relationship of WMH volume and infarcts in brain per MRI to MCI in 679 elderly persons without dementia. WMH was adjusted for total cranial volume, and MCI was defined using the Peterson criteria. WMH was more strongly related to aMCI (OR, 1.9) than nonamnestic MCI (OR, 1.6). However, infarcts were more strongly related to nonamnestic MCI (OR, 2.7) than aMCI (OR, 1.4). “In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with nonamnestic domains,” the researchers noted. “The nature of WMH in aMCI requires further study,” they concluded.
Intellectually normal children with seizures had neuropsychologic deficits at seizure onset, per a study published in the August 18 issue of Neurology. Investigators compared 282 children between ages 6 and 14 who had an IQ of 70 or higher and with a first recognized seizure to 147 healthy siblings. “In this intellectually normal cohort, 27% with just one seizure and up to 40% of those with risk factors exhibited neuropsychologic deficits at or near onset,” the researchers stated. Risk factors included multiple seizures (ie, second unprovoked seizure, odds ratio [OR], 1.96), use of antiepileptic drugs (OR, 2.27), symptomatic/cryptogenic etiology (OR, 2.15), and epileptiform activity on the initial EEG (OR, 1.96). Increased odds for neuropsychologic impairment were associated with absence epilepsy (OR, 2.00).
The H5N1 avian influenza virus may increase the risk for Parkinson’s disease and other neurologic disorders, according to a report in the August 10 online Proceedings of the National Academy of Sciences. In a mouse model, investigators showed that the virus travels from the peripheral nervous system into the CNS to higher levels of the neuroaxis. “In regions infected by H5N1 virus, we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection,” the researchers stated. A significant loss in dopaminergic neurons in the substantia nigra pars compacta was also observed, 60 days after infection. “Our results suggest that a pandemic H5N1 pathogen, or other neurotropic influenza virus, could initiate CNS disorders of protein aggregation including Parkinson’s and Alzheimer’s diseases,” the investigators concluded.
The FDA has approved Sabril (vigabatrin) tablets and oral solution for two difficult-to-treat epilepsies. Vigabatrin is indicated as monotherapy for pediatric patients ages 1 month to 2 years with infantile spasms for whom the potential benefits outweigh the potential risk of vision loss, and as adjunctive add-on therapy in adults with refractory complex partial seizures who have not responded to alternative treatments, and for whom the potential benefits outweigh the risk of vision loss. Vigabatrin use has been linked to permanent bilateral concentric visual field constriction in 30% or more of patients that ranges in severity from mild to severe. Vigabatrin is manufactured by Lundbeck, Inc (Deerfield, Illinois).
Compared with women without epilepsy, epileptic seizures during pregnancy increased the risk for low-birth-weight infants, preterm delivery, and small for gestational age by 1.36-fold, 1.63-fold, and 1.37-fold, respectively, according to a study in the August Archives of Neurology. Researchers in Taiwan matched 1,016 women with epilepsy with single births from 2001 to 2003 and who had been diagnosed with epilepsy in the two years prior to index delivery with 8,128 women without chronic disease. The authors then compared women with epilepsy who had seizures during pregnancy to women with epilepsy who did not have seizures and found that the risk of infants being small for gestational age increased most significantly (odds ratio, 1.34) among those who had seizures during pregnancy.
P2X7 receptor antagonist, Brilliant blue G (BBG), reduced spinal cord anatomic damage and improved motor recovery in rats without evident toxicity when administered 15 minutes after injury, researchers reported in the July 28 Proceedings of the National Academy of Sciences. Treatment with BBG, a derivative of a commonly used food color (FD&C blue No. 1) that is used to give M&Ms and Gatorade their blue tint, also directly reduced local activation of astrocytes and microglia, in addition to neutrophil infiltration. “These observations suggest that BBG not only protected spinal cord neurons from purinergic excitotoxicity, but also reduced local inflammatory responses,” investigators stated. “Systemic administration of BBG may thus comprise a readily feasible approach by which to treat spinal cord injury in humans.”
Although angiotensin-converting enzyme (ACE) inhibitors as a class do not appear to be associated with dementia risk or cognitive decline in older, hypertensive (HTN) adults, within-class differences may occur regarding these outcomes, suggests a study in the July 13 Archives of Internal Medicine. Investigators identified 158 cases of dementia among 414 participants who were exposed to ACE inhibitors and 640 who were not. There was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01). “However, centrally active ACE inhibitors were associated with 65% less decline in Modified Mini-Mental State Examination scores per year of exposure, and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20) and greater odds of disability in instrumental activities of daily living (adjusted OR, 1.16), compared with other anti-hypertension drugs,” investigators reported.
Researchers have found an association between the cytochrome P450 (CYP) 2C19*2 variant and diminished platelet response to clopidogrel treatment and poor cardiovascular outcomes, according to a study in the August 26 JAMA. Clopidogrel was administered for seven days to 429 healthy Amish persons. “Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance,” noted the study authors. “The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention.” In addition, those with the variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death in one year of follow-up.
Intramuscular AVI-4658 induces the expression of dystrophin, benefiting patients with Duchenne muscular dystrophy, according to a study in the August 26 online Lancet Neurology. Investigators assessed the safety of AVI-4658.Two patients received 0.09 mg AVI-4658 in 900 µl (0.9%) saline, and five received 0.9 mg AVI-4658 in 900 µl saline. “In randomly chosen sections of treated EDB muscles, the mean intensity of dystrophin staining ranged from 22% to 32% of the mean intensity of dystrophin in healthy control muscles (mean, 26.4%), and the mean intensity was 17% (range, 11% to 21%) greater than the intensity in the contralateral saline-treated muscle,” the researchers stated. “In the dystrophin-positive fibers, the intensity of dystrophin staining was up to 42% of that in healthy muscle.”
Higher diastolic blood pressure (DBP) is cross-sectionally and independently associated with cognitive impairment, investigators reported in the August 25 Neurology. The association was found after adjusting for economic factors, depressive symptoms, and current use of any antihyperintensive medication in 30,228 black and white men and women (45 and older). “An increment of 10 mm Hg in DBP was associated with a 7% higher odds of cognitive impairment,” the researchers stated. “No independent association was identified between impaired cognitive status and systolic blood pressure (odds ratio [OR], 1.02) or pulse pressure (OR, 0.99).” No evidence of nonlinear relationships between any blood pressure components and impaired cognitive status was found.
Use of smokeless tobacco products is associated with risk of fatal myocardial infarction and stroke, according to the August 18 online BMJ. Investigators from Sweden and the United States conducted a meta-analysis of 11 observational studies (primarily including men). “Eight risk estimates were available for fatal myocardial infarction: the relative risk for ever use of smokeless tobacco products was 1.13 and the excess risk was restricted to current users,” the investigators stated. “The relative risk of fatal stroke, on the basis of five risk estimates, was 1.40.” Increased risk of fatal myocardial infarction was shown in studies from both geographic locations. “Data on dose-response were limited but did not suggest a strong relation between risk of dying from either disease and frequency or duration of use of smokeless tobacco products,” the researchers noted.
A mutation in transcriptional repressor hDEC2-P385R is associated with a human short sleep phenotype, according to a study in the August 14 issue of Science. Investigators found that within a small extended family, two members with the mutation had lifelong shorter daily sleep requirements than most persons. The researchers then genetically engineered mice and fruit flies to express the mutated human gene and studied its impact on behavior and sleep patterns. “Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time- and sleep deprivation-dependent manner,” the study authors stated. “These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.”
The FDA has approved Extavia for reducing the frequency of clinical exacerbations in patients with relapsing forms of multiple sclerosis (MS). It is also indicated in patients who have had a first clinical episode of MS and have features consistent with the disease as shown by MRI. Extavia is a new branded version of interferon beta-1b and the same medicinal product as Betaseron. Interferon beta-1b has been shown to reduce annualized relapse rates by 34%, with patients nearly twice as likely to remain relapse-free for more than two years, compared with those receiving placebo. Injection site necrosis has been reported in 4% of patients in controlled trials, and anaphylaxis has been reported as a rare complication of interferon use. Extavia is marketed by the Pharmaceuticals Division of Novartis (East Hanover, NJ) and is expected to be available this fall.
White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (aMCI), and infarcts are more strongly related to nonamnestic MCI, according to a study in the August 11 issue of Neurology. Researchers investigated the relationship of WMH volume and infarcts in brain per MRI to MCI in 679 elderly persons without dementia. WMH was adjusted for total cranial volume, and MCI was defined using the Peterson criteria. WMH was more strongly related to aMCI (OR, 1.9) than nonamnestic MCI (OR, 1.6). However, infarcts were more strongly related to nonamnestic MCI (OR, 2.7) than aMCI (OR, 1.4). “In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with nonamnestic domains,” the researchers noted. “The nature of WMH in aMCI requires further study,” they concluded.
Intellectually normal children with seizures had neuropsychologic deficits at seizure onset, per a study published in the August 18 issue of Neurology. Investigators compared 282 children between ages 6 and 14 who had an IQ of 70 or higher and with a first recognized seizure to 147 healthy siblings. “In this intellectually normal cohort, 27% with just one seizure and up to 40% of those with risk factors exhibited neuropsychologic deficits at or near onset,” the researchers stated. Risk factors included multiple seizures (ie, second unprovoked seizure, odds ratio [OR], 1.96), use of antiepileptic drugs (OR, 2.27), symptomatic/cryptogenic etiology (OR, 2.15), and epileptiform activity on the initial EEG (OR, 1.96). Increased odds for neuropsychologic impairment were associated with absence epilepsy (OR, 2.00).
The H5N1 avian influenza virus may increase the risk for Parkinson’s disease and other neurologic disorders, according to a report in the August 10 online Proceedings of the National Academy of Sciences. In a mouse model, investigators showed that the virus travels from the peripheral nervous system into the CNS to higher levels of the neuroaxis. “In regions infected by H5N1 virus, we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection,” the researchers stated. A significant loss in dopaminergic neurons in the substantia nigra pars compacta was also observed, 60 days after infection. “Our results suggest that a pandemic H5N1 pathogen, or other neurotropic influenza virus, could initiate CNS disorders of protein aggregation including Parkinson’s and Alzheimer’s diseases,” the investigators concluded.
The FDA has approved Sabril (vigabatrin) tablets and oral solution for two difficult-to-treat epilepsies. Vigabatrin is indicated as monotherapy for pediatric patients ages 1 month to 2 years with infantile spasms for whom the potential benefits outweigh the potential risk of vision loss, and as adjunctive add-on therapy in adults with refractory complex partial seizures who have not responded to alternative treatments, and for whom the potential benefits outweigh the risk of vision loss. Vigabatrin use has been linked to permanent bilateral concentric visual field constriction in 30% or more of patients that ranges in severity from mild to severe. Vigabatrin is manufactured by Lundbeck, Inc (Deerfield, Illinois).
Compared with women without epilepsy, epileptic seizures during pregnancy increased the risk for low-birth-weight infants, preterm delivery, and small for gestational age by 1.36-fold, 1.63-fold, and 1.37-fold, respectively, according to a study in the August Archives of Neurology. Researchers in Taiwan matched 1,016 women with epilepsy with single births from 2001 to 2003 and who had been diagnosed with epilepsy in the two years prior to index delivery with 8,128 women without chronic disease. The authors then compared women with epilepsy who had seizures during pregnancy to women with epilepsy who did not have seizures and found that the risk of infants being small for gestational age increased most significantly (odds ratio, 1.34) among those who had seizures during pregnancy.
P2X7 receptor antagonist, Brilliant blue G (BBG), reduced spinal cord anatomic damage and improved motor recovery in rats without evident toxicity when administered 15 minutes after injury, researchers reported in the July 28 Proceedings of the National Academy of Sciences. Treatment with BBG, a derivative of a commonly used food color (FD&C blue No. 1) that is used to give M&Ms and Gatorade their blue tint, also directly reduced local activation of astrocytes and microglia, in addition to neutrophil infiltration. “These observations suggest that BBG not only protected spinal cord neurons from purinergic excitotoxicity, but also reduced local inflammatory responses,” investigators stated. “Systemic administration of BBG may thus comprise a readily feasible approach by which to treat spinal cord injury in humans.”
Although angiotensin-converting enzyme (ACE) inhibitors as a class do not appear to be associated with dementia risk or cognitive decline in older, hypertensive (HTN) adults, within-class differences may occur regarding these outcomes, suggests a study in the July 13 Archives of Internal Medicine. Investigators identified 158 cases of dementia among 414 participants who were exposed to ACE inhibitors and 640 who were not. There was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01). “However, centrally active ACE inhibitors were associated with 65% less decline in Modified Mini-Mental State Examination scores per year of exposure, and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20) and greater odds of disability in instrumental activities of daily living (adjusted OR, 1.16), compared with other anti-hypertension drugs,” investigators reported.
Researchers have found an association between the cytochrome P450 (CYP) 2C19*2 variant and diminished platelet response to clopidogrel treatment and poor cardiovascular outcomes, according to a study in the August 26 JAMA. Clopidogrel was administered for seven days to 429 healthy Amish persons. “Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance,” noted the study authors. “The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention.” In addition, those with the variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death in one year of follow-up.
Intramuscular AVI-4658 induces the expression of dystrophin, benefiting patients with Duchenne muscular dystrophy, according to a study in the August 26 online Lancet Neurology. Investigators assessed the safety of AVI-4658.Two patients received 0.09 mg AVI-4658 in 900 µl (0.9%) saline, and five received 0.9 mg AVI-4658 in 900 µl saline. “In randomly chosen sections of treated EDB muscles, the mean intensity of dystrophin staining ranged from 22% to 32% of the mean intensity of dystrophin in healthy control muscles (mean, 26.4%), and the mean intensity was 17% (range, 11% to 21%) greater than the intensity in the contralateral saline-treated muscle,” the researchers stated. “In the dystrophin-positive fibers, the intensity of dystrophin staining was up to 42% of that in healthy muscle.”
Higher diastolic blood pressure (DBP) is cross-sectionally and independently associated with cognitive impairment, investigators reported in the August 25 Neurology. The association was found after adjusting for economic factors, depressive symptoms, and current use of any antihyperintensive medication in 30,228 black and white men and women (45 and older). “An increment of 10 mm Hg in DBP was associated with a 7% higher odds of cognitive impairment,” the researchers stated. “No independent association was identified between impaired cognitive status and systolic blood pressure (odds ratio [OR], 1.02) or pulse pressure (OR, 0.99).” No evidence of nonlinear relationships between any blood pressure components and impaired cognitive status was found.
Use of smokeless tobacco products is associated with risk of fatal myocardial infarction and stroke, according to the August 18 online BMJ. Investigators from Sweden and the United States conducted a meta-analysis of 11 observational studies (primarily including men). “Eight risk estimates were available for fatal myocardial infarction: the relative risk for ever use of smokeless tobacco products was 1.13 and the excess risk was restricted to current users,” the investigators stated. “The relative risk of fatal stroke, on the basis of five risk estimates, was 1.40.” Increased risk of fatal myocardial infarction was shown in studies from both geographic locations. “Data on dose-response were limited but did not suggest a strong relation between risk of dying from either disease and frequency or duration of use of smokeless tobacco products,” the researchers noted.
A mutation in transcriptional repressor hDEC2-P385R is associated with a human short sleep phenotype, according to a study in the August 14 issue of Science. Investigators found that within a small extended family, two members with the mutation had lifelong shorter daily sleep requirements than most persons. The researchers then genetically engineered mice and fruit flies to express the mutated human gene and studied its impact on behavior and sleep patterns. “Activity profiles and sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice in a zeitgeber time- and sleep deprivation-dependent manner,” the study authors stated. “These mice represent a model of human sleep homeostasis that provides an opportunity to probe the effect of sleep on human physical and mental health.”
The FDA has approved Extavia for reducing the frequency of clinical exacerbations in patients with relapsing forms of multiple sclerosis (MS). It is also indicated in patients who have had a first clinical episode of MS and have features consistent with the disease as shown by MRI. Extavia is a new branded version of interferon beta-1b and the same medicinal product as Betaseron. Interferon beta-1b has been shown to reduce annualized relapse rates by 34%, with patients nearly twice as likely to remain relapse-free for more than two years, compared with those receiving placebo. Injection site necrosis has been reported in 4% of patients in controlled trials, and anaphylaxis has been reported as a rare complication of interferon use. Extavia is marketed by the Pharmaceuticals Division of Novartis (East Hanover, NJ) and is expected to be available this fall.
White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (aMCI), and infarcts are more strongly related to nonamnestic MCI, according to a study in the August 11 issue of Neurology. Researchers investigated the relationship of WMH volume and infarcts in brain per MRI to MCI in 679 elderly persons without dementia. WMH was adjusted for total cranial volume, and MCI was defined using the Peterson criteria. WMH was more strongly related to aMCI (OR, 1.9) than nonamnestic MCI (OR, 1.6). However, infarcts were more strongly related to nonamnestic MCI (OR, 2.7) than aMCI (OR, 1.4). “In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with nonamnestic domains,” the researchers noted. “The nature of WMH in aMCI requires further study,” they concluded.
Intellectually normal children with seizures had neuropsychologic deficits at seizure onset, per a study published in the August 18 issue of Neurology. Investigators compared 282 children between ages 6 and 14 who had an IQ of 70 or higher and with a first recognized seizure to 147 healthy siblings. “In this intellectually normal cohort, 27% with just one seizure and up to 40% of those with risk factors exhibited neuropsychologic deficits at or near onset,” the researchers stated. Risk factors included multiple seizures (ie, second unprovoked seizure, odds ratio [OR], 1.96), use of antiepileptic drugs (OR, 2.27), symptomatic/cryptogenic etiology (OR, 2.15), and epileptiform activity on the initial EEG (OR, 1.96). Increased odds for neuropsychologic impairment were associated with absence epilepsy (OR, 2.00).
The H5N1 avian influenza virus may increase the risk for Parkinson’s disease and other neurologic disorders, according to a report in the August 10 online Proceedings of the National Academy of Sciences. In a mouse model, investigators showed that the virus travels from the peripheral nervous system into the CNS to higher levels of the neuroaxis. “In regions infected by H5N1 virus, we observe activation of microglia and alpha-synuclein phosphorylation and aggregation that persists long after resolution of the infection,” the researchers stated. A significant loss in dopaminergic neurons in the substantia nigra pars compacta was also observed, 60 days after infection. “Our results suggest that a pandemic H5N1 pathogen, or other neurotropic influenza virus, could initiate CNS disorders of protein aggregation including Parkinson’s and Alzheimer’s diseases,” the investigators concluded.
The FDA has approved Sabril (vigabatrin) tablets and oral solution for two difficult-to-treat epilepsies. Vigabatrin is indicated as monotherapy for pediatric patients ages 1 month to 2 years with infantile spasms for whom the potential benefits outweigh the potential risk of vision loss, and as adjunctive add-on therapy in adults with refractory complex partial seizures who have not responded to alternative treatments, and for whom the potential benefits outweigh the risk of vision loss. Vigabatrin use has been linked to permanent bilateral concentric visual field constriction in 30% or more of patients that ranges in severity from mild to severe. Vigabatrin is manufactured by Lundbeck, Inc (Deerfield, Illinois).
Compared with women without epilepsy, epileptic seizures during pregnancy increased the risk for low-birth-weight infants, preterm delivery, and small for gestational age by 1.36-fold, 1.63-fold, and 1.37-fold, respectively, according to a study in the August Archives of Neurology. Researchers in Taiwan matched 1,016 women with epilepsy with single births from 2001 to 2003 and who had been diagnosed with epilepsy in the two years prior to index delivery with 8,128 women without chronic disease. The authors then compared women with epilepsy who had seizures during pregnancy to women with epilepsy who did not have seizures and found that the risk of infants being small for gestational age increased most significantly (odds ratio, 1.34) among those who had seizures during pregnancy.
P2X7 receptor antagonist, Brilliant blue G (BBG), reduced spinal cord anatomic damage and improved motor recovery in rats without evident toxicity when administered 15 minutes after injury, researchers reported in the July 28 Proceedings of the National Academy of Sciences. Treatment with BBG, a derivative of a commonly used food color (FD&C blue No. 1) that is used to give M&Ms and Gatorade their blue tint, also directly reduced local activation of astrocytes and microglia, in addition to neutrophil infiltration. “These observations suggest that BBG not only protected spinal cord neurons from purinergic excitotoxicity, but also reduced local inflammatory responses,” investigators stated. “Systemic administration of BBG may thus comprise a readily feasible approach by which to treat spinal cord injury in humans.”
Although angiotensin-converting enzyme (ACE) inhibitors as a class do not appear to be associated with dementia risk or cognitive decline in older, hypertensive (HTN) adults, within-class differences may occur regarding these outcomes, suggests a study in the July 13 Archives of Internal Medicine. Investigators identified 158 cases of dementia among 414 participants who were exposed to ACE inhibitors and 640 who were not. There was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01). “However, centrally active ACE inhibitors were associated with 65% less decline in Modified Mini-Mental State Examination scores per year of exposure, and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20) and greater odds of disability in instrumental activities of daily living (adjusted OR, 1.16), compared with other anti-hypertension drugs,” investigators reported.
Researchers have found an association between the cytochrome P450 (CYP) 2C19*2 variant and diminished platelet response to clopidogrel treatment and poor cardiovascular outcomes, according to a study in the August 26 JAMA. Clopidogrel was administered for seven days to 429 healthy Amish persons. “Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance,” noted the study authors. “The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention.” In addition, those with the variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death in one year of follow-up.
Intramuscular AVI-4658 induces the expression of dystrophin, benefiting patients with Duchenne muscular dystrophy, according to a study in the August 26 online Lancet Neurology. Investigators assessed the safety of AVI-4658.Two patients received 0.09 mg AVI-4658 in 900 µl (0.9%) saline, and five received 0.9 mg AVI-4658 in 900 µl saline. “In randomly chosen sections of treated EDB muscles, the mean intensity of dystrophin staining ranged from 22% to 32% of the mean intensity of dystrophin in healthy control muscles (mean, 26.4%), and the mean intensity was 17% (range, 11% to 21%) greater than the intensity in the contralateral saline-treated muscle,” the researchers stated. “In the dystrophin-positive fibers, the intensity of dystrophin staining was up to 42% of that in healthy muscle.”
Two MS Drug Studies Yield Divergent Clinical Findings
ATLANTA—A pair of studies directly comparing the effectiveness of interferon beta and glatiramer acetate for patients with multiple sclerosis (MS) have found contrasting results, which are dependent on the clinical criteria that are being measured.
In one study, interferon beta-1b was more effective than glatiramer acetate in limiting the conversion of newly enhancing lesions and acute black holes to chronic black holes, which are thought to represent irreversible damage in MS, reported Stuart D. Cook, MD, and colleagues in the August 16 online Journal of Neurology, Neurosurgery, and Psychiatry. However, the two-year risk of relapse was significantly lower in patients with MS who used glatiramer acetate than among those who used interferon beta-lb, interferon beta-1a IM, and interferon beta-1a SC, reported Kenneth P. Johnson, MD, and colleagues at the 2009 Joint Meeting of the Consortium of MS Centers and Americas Committee for Treatment and Research in MS.
Chronic Black Holes in MS
Dr. Cook’s group followed 75 patients with relapsing-remitting MS or a clinically isolated syndrome in the ongoing prospective, randomized Betaseron vs Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (BECOME) study. The researchers used monthly 3-Tesla brain MRI scans for up to two years to observe the development and evolution of new black holes in the participants, who were randomized to receive glatiramer acetate or interferon beta-1b.
A total of 1,224 newly enhancing lesions appearing at baseline through 24 months were observed in 61 patients; 767 (62.7%) lesions showed an acute black hole. “The majority of acute black holes were transient and of similar duration by treatment group,” stated Dr. Cook, Professor of Neurosciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School in Newark, and coauthors. “Black holes are more common in patients with secondary progression than with relapsing-remitting MS and in aggressive than in benign MS.”
Follow-up scans were available for one year or more regarding 571 acute black holes. The investigators found that 103 (18.8%) black holes were still visible 12 or more months after onset and were thus characterized as chronic black holes. About 12% of the 849 newly enhancing lesions with MRI follow-up for one or more years converted to chronic black holes—9.8% with interferon beta-1b and 15.2% with glatiramer acetate. In addition, the conversion rate from acute black holes to chronic black holes was also lower with interferon beta-1b (15.2%) than with glatiramer acetate (21.4%).
“Although we did find a significantly lower conversion rate from newly enhancing lesions to chronic black holes in brain lesions that develop in patients randomized to interferon beta-1b compared to glatiramer acetate, the difference was modest,” Dr. Cook and colleagues reported. “However, this was an unexpected finding because of the widespread belief in the MS field that glatiramer acetate, but not interferon beta-1b, is neuroprotective. The analysis of the primary outcome of BECOME showed no differences by treatment group in brain MRI activity over one year or in new brain lesion formation or annualized relapse rates over two years.
“Although our study of black holes supports the view that extensive repair takes place in the majority of new brain lesions that occur in relapsing-remitting MS patients treated with first-line disease modifying therapies, it remains to be determined whether similar repair takes place in normal appearing white and gray matter and why lesion repair appears to fail over time in many patients and even early on in some patients.”
Dr. Cook noted that patients with MS are usually started on an interferon beta or glatiramer acetate, but “all are effective drugs,” he told Neurology Reviews. “There are advantages and disadvantages of each drug. Patients and physicians need to discuss the options to select the best drug based on efficacy and tolerability. All are very safe.
“As yet, there is insufficient long-term clinical data to support choosing an interferon versus glatiramer acetate. Recent studies support possible MRI benefit of interferons—for example, the REGARD, BEYOND, and BECOME studies.”
Relapse Rates in MS
Dr. Johnson’s group identified 51,162 patients with MS from an administrative claims database. The investigators conducted a series of pair-wise comparisons between patients who used glatiramer acetate and those who used each of the three interferon beta drugs under usual care conditions in the trial, which was not randomized or prospective. Demographic profiles of participants among the four treatment groups were similar, and no differences regarding use of immunomodulators was observed among patients from various geographic regions. Relapse was defined as either hospitalization with a primary diagnosis of MS or an outpatient visit with a diagnosis of MS accompanied by a prescription for steroids within seven days after the outpatient visit.
The researchers found that the two-year risk of relapse for patients who had received glatiramer acetate was 5.3%, compared with a rate of 13.5% in those who had received interferon beta-1b. The two-year risk of relapse for those who had taken glatiramer acetate was 5.2%, versus a rate of 10% among those who used interferon beta-1a IM. The two-year risk of relapse was 5.9% in those who had used glatiramer acetate, compared with 10.9% in those who had taken interferon beta-1a SC.
“In this recent comparison of immunomodulators for MS, the two-year risk of relapse was significantly lower for glatiramer acetate than for any of the three interferon beta drugs,” stated Dr. Johnson, Professor Emeritus of Neurology, University of Maryland, and Program Director of the Maryland Center for MS in Baltimore. “Nationwide outcomes came from treating physicians’ personal treatment decisions, free of drug company–sponsored studies or programs.”
In an interview with Neurology Reviews, Dr. Johnson said, “[Our] data show that in the broad population of patients across the US, glatiramer acetate works better than any of the interferons and is less costly, but it doesn’t work in every patient. We’re just now beginning to figure out which patients respond to which drugs.
“My recommendation,” advised Dr. Johnson, “is to start with glatiramer acetate, and if the patients do well, and probably around 60% of them will do well, then that’s the drug of choice. But for those patients who seem to respond poorly, we now have other choices.
“There are several problems with interferons that don’t occur with glatiramer acetate,” he continued. “Depending on the interferon, as many as a third of patients may develop neutralizing antibodies, in which case the drug is no longer effective. Rare patients develop liver toxicity and have to be taken off the interferon. So there are some indications for wanting to take patients off interferon. But if they’re doing well, there is no reason to do that. Interferons have been tested long enough [for clinicians] to know that they are effective but not as effective as glatiramer acetate, and they have more problems and more side effects.”
Dr. Johnson pointed out that it is important to differentiate between efficacy and effectiveness when interpreting his study’s results. Efficacy is the finding from a [specific] population of patients like we define in clinical trials, and in those situations the drugs were probably more or less equal,” he said. “However, in effectiveness, which is the broad category of patients in the US population with any disease, the effectiveness may not be the same as efficacy, and that’s why these findings are coming out the way they are.”
Suggested Reading
Cadavid D, Cheriyan J, Skurnick J, et al. New acute and chronic black holes in multiple sclerosis patients randomized to interferon beta-1b or glatiramer acetate. J Neurol Neurosurg Psychiatry. 2009 Aug 16; [Epub ahead of print].
Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72(23):1976-1983.
Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7(10):903-914.
ATLANTA—A pair of studies directly comparing the effectiveness of interferon beta and glatiramer acetate for patients with multiple sclerosis (MS) have found contrasting results, which are dependent on the clinical criteria that are being measured.
In one study, interferon beta-1b was more effective than glatiramer acetate in limiting the conversion of newly enhancing lesions and acute black holes to chronic black holes, which are thought to represent irreversible damage in MS, reported Stuart D. Cook, MD, and colleagues in the August 16 online Journal of Neurology, Neurosurgery, and Psychiatry. However, the two-year risk of relapse was significantly lower in patients with MS who used glatiramer acetate than among those who used interferon beta-lb, interferon beta-1a IM, and interferon beta-1a SC, reported Kenneth P. Johnson, MD, and colleagues at the 2009 Joint Meeting of the Consortium of MS Centers and Americas Committee for Treatment and Research in MS.
Chronic Black Holes in MS
Dr. Cook’s group followed 75 patients with relapsing-remitting MS or a clinically isolated syndrome in the ongoing prospective, randomized Betaseron vs Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (BECOME) study. The researchers used monthly 3-Tesla brain MRI scans for up to two years to observe the development and evolution of new black holes in the participants, who were randomized to receive glatiramer acetate or interferon beta-1b.
A total of 1,224 newly enhancing lesions appearing at baseline through 24 months were observed in 61 patients; 767 (62.7%) lesions showed an acute black hole. “The majority of acute black holes were transient and of similar duration by treatment group,” stated Dr. Cook, Professor of Neurosciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School in Newark, and coauthors. “Black holes are more common in patients with secondary progression than with relapsing-remitting MS and in aggressive than in benign MS.”
Follow-up scans were available for one year or more regarding 571 acute black holes. The investigators found that 103 (18.8%) black holes were still visible 12 or more months after onset and were thus characterized as chronic black holes. About 12% of the 849 newly enhancing lesions with MRI follow-up for one or more years converted to chronic black holes—9.8% with interferon beta-1b and 15.2% with glatiramer acetate. In addition, the conversion rate from acute black holes to chronic black holes was also lower with interferon beta-1b (15.2%) than with glatiramer acetate (21.4%).
“Although we did find a significantly lower conversion rate from newly enhancing lesions to chronic black holes in brain lesions that develop in patients randomized to interferon beta-1b compared to glatiramer acetate, the difference was modest,” Dr. Cook and colleagues reported. “However, this was an unexpected finding because of the widespread belief in the MS field that glatiramer acetate, but not interferon beta-1b, is neuroprotective. The analysis of the primary outcome of BECOME showed no differences by treatment group in brain MRI activity over one year or in new brain lesion formation or annualized relapse rates over two years.
“Although our study of black holes supports the view that extensive repair takes place in the majority of new brain lesions that occur in relapsing-remitting MS patients treated with first-line disease modifying therapies, it remains to be determined whether similar repair takes place in normal appearing white and gray matter and why lesion repair appears to fail over time in many patients and even early on in some patients.”
Dr. Cook noted that patients with MS are usually started on an interferon beta or glatiramer acetate, but “all are effective drugs,” he told Neurology Reviews. “There are advantages and disadvantages of each drug. Patients and physicians need to discuss the options to select the best drug based on efficacy and tolerability. All are very safe.
“As yet, there is insufficient long-term clinical data to support choosing an interferon versus glatiramer acetate. Recent studies support possible MRI benefit of interferons—for example, the REGARD, BEYOND, and BECOME studies.”
Relapse Rates in MS
Dr. Johnson’s group identified 51,162 patients with MS from an administrative claims database. The investigators conducted a series of pair-wise comparisons between patients who used glatiramer acetate and those who used each of the three interferon beta drugs under usual care conditions in the trial, which was not randomized or prospective. Demographic profiles of participants among the four treatment groups were similar, and no differences regarding use of immunomodulators was observed among patients from various geographic regions. Relapse was defined as either hospitalization with a primary diagnosis of MS or an outpatient visit with a diagnosis of MS accompanied by a prescription for steroids within seven days after the outpatient visit.
The researchers found that the two-year risk of relapse for patients who had received glatiramer acetate was 5.3%, compared with a rate of 13.5% in those who had received interferon beta-1b. The two-year risk of relapse for those who had taken glatiramer acetate was 5.2%, versus a rate of 10% among those who used interferon beta-1a IM. The two-year risk of relapse was 5.9% in those who had used glatiramer acetate, compared with 10.9% in those who had taken interferon beta-1a SC.
“In this recent comparison of immunomodulators for MS, the two-year risk of relapse was significantly lower for glatiramer acetate than for any of the three interferon beta drugs,” stated Dr. Johnson, Professor Emeritus of Neurology, University of Maryland, and Program Director of the Maryland Center for MS in Baltimore. “Nationwide outcomes came from treating physicians’ personal treatment decisions, free of drug company–sponsored studies or programs.”
In an interview with Neurology Reviews, Dr. Johnson said, “[Our] data show that in the broad population of patients across the US, glatiramer acetate works better than any of the interferons and is less costly, but it doesn’t work in every patient. We’re just now beginning to figure out which patients respond to which drugs.
“My recommendation,” advised Dr. Johnson, “is to start with glatiramer acetate, and if the patients do well, and probably around 60% of them will do well, then that’s the drug of choice. But for those patients who seem to respond poorly, we now have other choices.
“There are several problems with interferons that don’t occur with glatiramer acetate,” he continued. “Depending on the interferon, as many as a third of patients may develop neutralizing antibodies, in which case the drug is no longer effective. Rare patients develop liver toxicity and have to be taken off the interferon. So there are some indications for wanting to take patients off interferon. But if they’re doing well, there is no reason to do that. Interferons have been tested long enough [for clinicians] to know that they are effective but not as effective as glatiramer acetate, and they have more problems and more side effects.”
Dr. Johnson pointed out that it is important to differentiate between efficacy and effectiveness when interpreting his study’s results. Efficacy is the finding from a [specific] population of patients like we define in clinical trials, and in those situations the drugs were probably more or less equal,” he said. “However, in effectiveness, which is the broad category of patients in the US population with any disease, the effectiveness may not be the same as efficacy, and that’s why these findings are coming out the way they are.”
ATLANTA—A pair of studies directly comparing the effectiveness of interferon beta and glatiramer acetate for patients with multiple sclerosis (MS) have found contrasting results, which are dependent on the clinical criteria that are being measured.
In one study, interferon beta-1b was more effective than glatiramer acetate in limiting the conversion of newly enhancing lesions and acute black holes to chronic black holes, which are thought to represent irreversible damage in MS, reported Stuart D. Cook, MD, and colleagues in the August 16 online Journal of Neurology, Neurosurgery, and Psychiatry. However, the two-year risk of relapse was significantly lower in patients with MS who used glatiramer acetate than among those who used interferon beta-lb, interferon beta-1a IM, and interferon beta-1a SC, reported Kenneth P. Johnson, MD, and colleagues at the 2009 Joint Meeting of the Consortium of MS Centers and Americas Committee for Treatment and Research in MS.
Chronic Black Holes in MS
Dr. Cook’s group followed 75 patients with relapsing-remitting MS or a clinically isolated syndrome in the ongoing prospective, randomized Betaseron vs Copaxone in MS with Triple-Dose Gadolinium and 3-T MRI Endpoints (BECOME) study. The researchers used monthly 3-Tesla brain MRI scans for up to two years to observe the development and evolution of new black holes in the participants, who were randomized to receive glatiramer acetate or interferon beta-1b.
A total of 1,224 newly enhancing lesions appearing at baseline through 24 months were observed in 61 patients; 767 (62.7%) lesions showed an acute black hole. “The majority of acute black holes were transient and of similar duration by treatment group,” stated Dr. Cook, Professor of Neurosciences, University of Medicine and Dentistry of New Jersey, New Jersey Medical School in Newark, and coauthors. “Black holes are more common in patients with secondary progression than with relapsing-remitting MS and in aggressive than in benign MS.”
Follow-up scans were available for one year or more regarding 571 acute black holes. The investigators found that 103 (18.8%) black holes were still visible 12 or more months after onset and were thus characterized as chronic black holes. About 12% of the 849 newly enhancing lesions with MRI follow-up for one or more years converted to chronic black holes—9.8% with interferon beta-1b and 15.2% with glatiramer acetate. In addition, the conversion rate from acute black holes to chronic black holes was also lower with interferon beta-1b (15.2%) than with glatiramer acetate (21.4%).
“Although we did find a significantly lower conversion rate from newly enhancing lesions to chronic black holes in brain lesions that develop in patients randomized to interferon beta-1b compared to glatiramer acetate, the difference was modest,” Dr. Cook and colleagues reported. “However, this was an unexpected finding because of the widespread belief in the MS field that glatiramer acetate, but not interferon beta-1b, is neuroprotective. The analysis of the primary outcome of BECOME showed no differences by treatment group in brain MRI activity over one year or in new brain lesion formation or annualized relapse rates over two years.
“Although our study of black holes supports the view that extensive repair takes place in the majority of new brain lesions that occur in relapsing-remitting MS patients treated with first-line disease modifying therapies, it remains to be determined whether similar repair takes place in normal appearing white and gray matter and why lesion repair appears to fail over time in many patients and even early on in some patients.”
Dr. Cook noted that patients with MS are usually started on an interferon beta or glatiramer acetate, but “all are effective drugs,” he told Neurology Reviews. “There are advantages and disadvantages of each drug. Patients and physicians need to discuss the options to select the best drug based on efficacy and tolerability. All are very safe.
“As yet, there is insufficient long-term clinical data to support choosing an interferon versus glatiramer acetate. Recent studies support possible MRI benefit of interferons—for example, the REGARD, BEYOND, and BECOME studies.”
Relapse Rates in MS
Dr. Johnson’s group identified 51,162 patients with MS from an administrative claims database. The investigators conducted a series of pair-wise comparisons between patients who used glatiramer acetate and those who used each of the three interferon beta drugs under usual care conditions in the trial, which was not randomized or prospective. Demographic profiles of participants among the four treatment groups were similar, and no differences regarding use of immunomodulators was observed among patients from various geographic regions. Relapse was defined as either hospitalization with a primary diagnosis of MS or an outpatient visit with a diagnosis of MS accompanied by a prescription for steroids within seven days after the outpatient visit.
The researchers found that the two-year risk of relapse for patients who had received glatiramer acetate was 5.3%, compared with a rate of 13.5% in those who had received interferon beta-1b. The two-year risk of relapse for those who had taken glatiramer acetate was 5.2%, versus a rate of 10% among those who used interferon beta-1a IM. The two-year risk of relapse was 5.9% in those who had used glatiramer acetate, compared with 10.9% in those who had taken interferon beta-1a SC.
“In this recent comparison of immunomodulators for MS, the two-year risk of relapse was significantly lower for glatiramer acetate than for any of the three interferon beta drugs,” stated Dr. Johnson, Professor Emeritus of Neurology, University of Maryland, and Program Director of the Maryland Center for MS in Baltimore. “Nationwide outcomes came from treating physicians’ personal treatment decisions, free of drug company–sponsored studies or programs.”
In an interview with Neurology Reviews, Dr. Johnson said, “[Our] data show that in the broad population of patients across the US, glatiramer acetate works better than any of the interferons and is less costly, but it doesn’t work in every patient. We’re just now beginning to figure out which patients respond to which drugs.
“My recommendation,” advised Dr. Johnson, “is to start with glatiramer acetate, and if the patients do well, and probably around 60% of them will do well, then that’s the drug of choice. But for those patients who seem to respond poorly, we now have other choices.
“There are several problems with interferons that don’t occur with glatiramer acetate,” he continued. “Depending on the interferon, as many as a third of patients may develop neutralizing antibodies, in which case the drug is no longer effective. Rare patients develop liver toxicity and have to be taken off the interferon. So there are some indications for wanting to take patients off interferon. But if they’re doing well, there is no reason to do that. Interferons have been tested long enough [for clinicians] to know that they are effective but not as effective as glatiramer acetate, and they have more problems and more side effects.”
Dr. Johnson pointed out that it is important to differentiate between efficacy and effectiveness when interpreting his study’s results. Efficacy is the finding from a [specific] population of patients like we define in clinical trials, and in those situations the drugs were probably more or less equal,” he said. “However, in effectiveness, which is the broad category of patients in the US population with any disease, the effectiveness may not be the same as efficacy, and that’s why these findings are coming out the way they are.”
Suggested Reading
Cadavid D, Cheriyan J, Skurnick J, et al. New acute and chronic black holes in multiple sclerosis patients randomized to interferon beta-1b or glatiramer acetate. J Neurol Neurosurg Psychiatry. 2009 Aug 16; [Epub ahead of print].
Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72(23):1976-1983.
Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7(10):903-914.
Suggested Reading
Cadavid D, Cheriyan J, Skurnick J, et al. New acute and chronic black holes in multiple sclerosis patients randomized to interferon beta-1b or glatiramer acetate. J Neurol Neurosurg Psychiatry. 2009 Aug 16; [Epub ahead of print].
Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72(23):1976-1983.
Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7(10):903-914.
Risk Factors for MS in Children—Do Environmental Conditions Have a Causal Role?
Epstein-Barr virus, exposure to cigarette smoke, and vitamin D deficiency in children may increase the risk for adult-onset MS. A leading researcher reviews the data for these potential causes.
ATLANTA—Environmental risk factors—such as Epstein Barr virus (EBV) infection, exposure to cigarette smoke, and vitamin D deficiency—may contribute to the development of multiple sclerosis (MS) in children, reported Kassandra L. Munger, ScD, at the 2009 Joint Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
One challenge to studying risk factors for MS in children is that childhood-onset MS is rare, according to Dr. Munger, a doctoral candidate and Research Associate in the Department of Nutrition at Harvard School of Public Health in Boston. About 2% to 10% of all patients with MS are diagnosed before age 18. Therefore, studies have small sample sizes, with low statistical power, and tend to be a case-control design, which has many limitations, such as recall bias, selection bias, and reverse causation.
Studies in adults have shown a strong link between environmental risk factors and development of MS. Most epidemiologic evidence points toward EBV infection, exposure to cigarette smoke, and vitamin D deficiency as risk factors. EBV infection and cigarette smoking have been studied as risk factors for pediatric MS, noted Dr. Munger.
EBV Infection
Most people become infected with EBV during childhood; however, some individuals contract the virus during adolescence or early adulthood and are more likely to have symptomatic infection that will manifest as infectious mononucleosis. Similarities between the epidemiology of infectious mononucleosis and MS “have prompted investigators to examine whether a history of infectious mononucleosis is associated with MS risk,” Dr. Munger commented.
A meta-analysis published in 2006 found that infectious mononucleosis was associated with a more than twofold increased risk of MS. Since then, three other studies have been published—one in Denmark, one in the Netherlands, and one in Canada. “All three studies also found a greater than twofold increased risk associated with having had infectious mononucleosis,” Dr. Munger noted.
Several other studies have looked at anti-EBV antibodies and risk of MS. These studies have demonstrated a two- to ninefold increased risk of MS with elevated IgG antibodies against Epstein Barr nuclear antigens detected up to 16 to 20 years prior to MS onset.
In a meta-analysis investigating seropositivity for EBV in MS cases, 0.5% of cases were EBV-negative, compared with 6% of controls. “So being EBV-negative is associated with a 94% reduced risk of MS,” said Dr. Munger.
The association between EBV infection and risk of MS has been examined in some pediatric populations, added Dr. Munger. In a Canadian study involving 30 MS cases (mean age of onset, 12) and 90 matched controls, blood samples were collected within 1.5 years after onset of MS. Researchers found that 83% of MS cases had a history of past EBV infection, compared with 42% of controls. “So there was a greater than eightfold increased risk of MS associated with having past EBV infection,” she noted.
In a study conducted in Germany including 147 MS cases (mean age of onset, 12) and 147 matched controls, blood samples were collected an average of one year after onset of MS. More than 80% of children with MS had a history of past EBV infection, compared with 56% of controls. In addition, children with MS had higher antibody titers to viral capsid antigen and Epstein Barr nuclear antigen.
Furthermore, in a study of 96 MS cases and 96 controls from centers in North and South America, Banwell et al demonstrated that more than 80% of cases had evidence of past EBV infection, compared with 60% of controls.
“These studies strengthen the evidence that EBV may have a causal role in MS; however, confirmation in larger studies in additional populations is needed,” stated Dr. Munger.
Exposure to Cigarette Smoke
Cigarette smoking has also been implicated in the development of MS, and findings provide strong motivation for not smoking among individuals at high risk for MS, said Dr. Munger.
In a meta-analysis of prospective studies, ever smoking was associated with a 50% increased risk of MS. In addition, in the Nurses Health Study cohorts, women with one to nine pack-years of smoking had no increased risk of MS, whereas women with 10 to 24 pack-years or 25 or more pack-years of smoking had a 50% to 70% increased risk of MS.
One study of pediatric MS examined whether parental smoking was associated with risk of MS in offspring. A total of 129 confirmed cases of MS with onset before age 16 and 1,038 matched controls were included. Participants were asked if one or both parents smoked within the home before the date of MS onset or before the index date in controls. Findings demonstrated that 62% of MS cases were exposed to parental cigarette smoking, compared with 45% of matched controls. This represented a twofold increased risk of MS in children who were exposed to cigarette smoking. However, these results may be explained by recall or selection bias, she noted.
However, in another study conducted in Sweden, Montgomery et al. found that maternal smoking during pregnancy was not associated with an increased risk of MS in offspring diagnosed with MS before age 16.
Vitamin D Exposure
No studies of vitamin D exposure in pediatric MS have been published, stated Dr. Munger. However, several prospective studies in adults have looked at vitamin D by measuring sun exposure, dietary intake, and levels of serum 25-hydroxyvitamin D [25(OH)D] levels, which are an integrated measure of both sun and dietary sources. Dr. Munger noted that several case-control studies have examined vitamin D exposure in childhood and risk of developing MS as an adult. In one study conducted in Tasmania, Australia, researchers found a 50% to 60% reduced risk of MS with more than four hours of sun exposure between ages 6 and 10. In another study conducted in northern Norway, greater time spent outdoors in the summer between ages 16 and 20 was associated with a 50% reduced risk of MS. In addition, consuming fish—a primary dietary source of vitamin D—more than three times per week was associated with a 50% reduced risk of MS in this cohort. Also, in a study conducted in North America, time spent outdoors in the summer or time spent sun tanning in childhood was associated with a 60% reduced risk of MS.
Because these are case-control studies, “we have to consider that these associations could be explained by recall bias or selection bias,” said Dr. Munger. She also pointed out that another limitation of these studies is that sun exposure is not a direct measure of vitamin D exposure.
The strongest evidence to date that vitamin D may reduce MS risk comes from two prospective studies. The first, among women in the Nurses’ Health Study cohorts, found that women with a dietary intake of at least 400 IU/day of vitamin D had a 40% reduced risk of MS. The main limitation of this study, however, is that diet contributes little to the overall vitamin D nutritional status. Therefore, in the second study, vitamin D exposure was measured by blood levels of 25(OH)D in healthy young adults in the US military. Among whites, levels of 25(OH)D greater than 100 nmol/L were associated with a 50% reduced risk of MS, compared with those with levels less than 75 nmol/L. Whether adequate vitamin D nutrition is associated with a reduced risk of pediatric MS is an important question and one that is currently being studied.
Other Associations With MS Risk
“There have been some other factors in pediatric-onset MS that have been looked at,” said Dr. Munger. In a study conducted in France, researchers assessed the association between hepatitis B vaccination and pediatric-onset MS. An assessment of 143 MS cases with onset before age 16 and 1,122 matched controls showed that neither the timing nor the number of hepatitis B vaccinations was associated with MS risk. However, in a follow-up study, one specific brand of hepatitis B vaccine was associated with a threefold increased risk for MS three years after the last vaccine dose.
In the same population, researchers found that chicken pox appeared to be protective against MS, with 77% of MS cases reporting a history of clinically observed chicken pox, compared with 85% of controls.
Current evidence supports a link between EBV infection and pediatric-onset MS. Studies examining exposure to cigarette smoke and pediatric MS risk are conflicting and more studies are warranted. While there is growing evidence that vitamin D may decrease MS risk among adults, there are currently no studies in pediatric MS. A history of clinically observed chicken pox appears to be protective, and the association between hepatitis B vaccination and pediatric-onset MS remains unclear. However, confirmation of all these findings is needed in larger studies, concluded Dr. Munger.
—Karen L. Spittler
Suggested Reading
Banwell BL. Through the eyes of a child: research insights gained through the study of childhood multiple sclerosis. Mult Scler. 2008;14(1):4-5.
Epstein-Barr virus, exposure to cigarette smoke, and vitamin D deficiency in children may increase the risk for adult-onset MS. A leading researcher reviews the data for these potential causes.
ATLANTA—Environmental risk factors—such as Epstein Barr virus (EBV) infection, exposure to cigarette smoke, and vitamin D deficiency—may contribute to the development of multiple sclerosis (MS) in children, reported Kassandra L. Munger, ScD, at the 2009 Joint Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
One challenge to studying risk factors for MS in children is that childhood-onset MS is rare, according to Dr. Munger, a doctoral candidate and Research Associate in the Department of Nutrition at Harvard School of Public Health in Boston. About 2% to 10% of all patients with MS are diagnosed before age 18. Therefore, studies have small sample sizes, with low statistical power, and tend to be a case-control design, which has many limitations, such as recall bias, selection bias, and reverse causation.
Studies in adults have shown a strong link between environmental risk factors and development of MS. Most epidemiologic evidence points toward EBV infection, exposure to cigarette smoke, and vitamin D deficiency as risk factors. EBV infection and cigarette smoking have been studied as risk factors for pediatric MS, noted Dr. Munger.
EBV Infection
Most people become infected with EBV during childhood; however, some individuals contract the virus during adolescence or early adulthood and are more likely to have symptomatic infection that will manifest as infectious mononucleosis. Similarities between the epidemiology of infectious mononucleosis and MS “have prompted investigators to examine whether a history of infectious mononucleosis is associated with MS risk,” Dr. Munger commented.
A meta-analysis published in 2006 found that infectious mononucleosis was associated with a more than twofold increased risk of MS. Since then, three other studies have been published—one in Denmark, one in the Netherlands, and one in Canada. “All three studies also found a greater than twofold increased risk associated with having had infectious mononucleosis,” Dr. Munger noted.
Several other studies have looked at anti-EBV antibodies and risk of MS. These studies have demonstrated a two- to ninefold increased risk of MS with elevated IgG antibodies against Epstein Barr nuclear antigens detected up to 16 to 20 years prior to MS onset.
In a meta-analysis investigating seropositivity for EBV in MS cases, 0.5% of cases were EBV-negative, compared with 6% of controls. “So being EBV-negative is associated with a 94% reduced risk of MS,” said Dr. Munger.
The association between EBV infection and risk of MS has been examined in some pediatric populations, added Dr. Munger. In a Canadian study involving 30 MS cases (mean age of onset, 12) and 90 matched controls, blood samples were collected within 1.5 years after onset of MS. Researchers found that 83% of MS cases had a history of past EBV infection, compared with 42% of controls. “So there was a greater than eightfold increased risk of MS associated with having past EBV infection,” she noted.
In a study conducted in Germany including 147 MS cases (mean age of onset, 12) and 147 matched controls, blood samples were collected an average of one year after onset of MS. More than 80% of children with MS had a history of past EBV infection, compared with 56% of controls. In addition, children with MS had higher antibody titers to viral capsid antigen and Epstein Barr nuclear antigen.
Furthermore, in a study of 96 MS cases and 96 controls from centers in North and South America, Banwell et al demonstrated that more than 80% of cases had evidence of past EBV infection, compared with 60% of controls.
“These studies strengthen the evidence that EBV may have a causal role in MS; however, confirmation in larger studies in additional populations is needed,” stated Dr. Munger.
Exposure to Cigarette Smoke
Cigarette smoking has also been implicated in the development of MS, and findings provide strong motivation for not smoking among individuals at high risk for MS, said Dr. Munger.
In a meta-analysis of prospective studies, ever smoking was associated with a 50% increased risk of MS. In addition, in the Nurses Health Study cohorts, women with one to nine pack-years of smoking had no increased risk of MS, whereas women with 10 to 24 pack-years or 25 or more pack-years of smoking had a 50% to 70% increased risk of MS.
One study of pediatric MS examined whether parental smoking was associated with risk of MS in offspring. A total of 129 confirmed cases of MS with onset before age 16 and 1,038 matched controls were included. Participants were asked if one or both parents smoked within the home before the date of MS onset or before the index date in controls. Findings demonstrated that 62% of MS cases were exposed to parental cigarette smoking, compared with 45% of matched controls. This represented a twofold increased risk of MS in children who were exposed to cigarette smoking. However, these results may be explained by recall or selection bias, she noted.
However, in another study conducted in Sweden, Montgomery et al. found that maternal smoking during pregnancy was not associated with an increased risk of MS in offspring diagnosed with MS before age 16.
Vitamin D Exposure
No studies of vitamin D exposure in pediatric MS have been published, stated Dr. Munger. However, several prospective studies in adults have looked at vitamin D by measuring sun exposure, dietary intake, and levels of serum 25-hydroxyvitamin D [25(OH)D] levels, which are an integrated measure of both sun and dietary sources. Dr. Munger noted that several case-control studies have examined vitamin D exposure in childhood and risk of developing MS as an adult. In one study conducted in Tasmania, Australia, researchers found a 50% to 60% reduced risk of MS with more than four hours of sun exposure between ages 6 and 10. In another study conducted in northern Norway, greater time spent outdoors in the summer between ages 16 and 20 was associated with a 50% reduced risk of MS. In addition, consuming fish—a primary dietary source of vitamin D—more than three times per week was associated with a 50% reduced risk of MS in this cohort. Also, in a study conducted in North America, time spent outdoors in the summer or time spent sun tanning in childhood was associated with a 60% reduced risk of MS.
Because these are case-control studies, “we have to consider that these associations could be explained by recall bias or selection bias,” said Dr. Munger. She also pointed out that another limitation of these studies is that sun exposure is not a direct measure of vitamin D exposure.
The strongest evidence to date that vitamin D may reduce MS risk comes from two prospective studies. The first, among women in the Nurses’ Health Study cohorts, found that women with a dietary intake of at least 400 IU/day of vitamin D had a 40% reduced risk of MS. The main limitation of this study, however, is that diet contributes little to the overall vitamin D nutritional status. Therefore, in the second study, vitamin D exposure was measured by blood levels of 25(OH)D in healthy young adults in the US military. Among whites, levels of 25(OH)D greater than 100 nmol/L were associated with a 50% reduced risk of MS, compared with those with levels less than 75 nmol/L. Whether adequate vitamin D nutrition is associated with a reduced risk of pediatric MS is an important question and one that is currently being studied.
Other Associations With MS Risk
“There have been some other factors in pediatric-onset MS that have been looked at,” said Dr. Munger. In a study conducted in France, researchers assessed the association between hepatitis B vaccination and pediatric-onset MS. An assessment of 143 MS cases with onset before age 16 and 1,122 matched controls showed that neither the timing nor the number of hepatitis B vaccinations was associated with MS risk. However, in a follow-up study, one specific brand of hepatitis B vaccine was associated with a threefold increased risk for MS three years after the last vaccine dose.
In the same population, researchers found that chicken pox appeared to be protective against MS, with 77% of MS cases reporting a history of clinically observed chicken pox, compared with 85% of controls.
Current evidence supports a link between EBV infection and pediatric-onset MS. Studies examining exposure to cigarette smoke and pediatric MS risk are conflicting and more studies are warranted. While there is growing evidence that vitamin D may decrease MS risk among adults, there are currently no studies in pediatric MS. A history of clinically observed chicken pox appears to be protective, and the association between hepatitis B vaccination and pediatric-onset MS remains unclear. However, confirmation of all these findings is needed in larger studies, concluded Dr. Munger.
—Karen L. Spittler
Epstein-Barr virus, exposure to cigarette smoke, and vitamin D deficiency in children may increase the risk for adult-onset MS. A leading researcher reviews the data for these potential causes.
ATLANTA—Environmental risk factors—such as Epstein Barr virus (EBV) infection, exposure to cigarette smoke, and vitamin D deficiency—may contribute to the development of multiple sclerosis (MS) in children, reported Kassandra L. Munger, ScD, at the 2009 Joint Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis.
One challenge to studying risk factors for MS in children is that childhood-onset MS is rare, according to Dr. Munger, a doctoral candidate and Research Associate in the Department of Nutrition at Harvard School of Public Health in Boston. About 2% to 10% of all patients with MS are diagnosed before age 18. Therefore, studies have small sample sizes, with low statistical power, and tend to be a case-control design, which has many limitations, such as recall bias, selection bias, and reverse causation.
Studies in adults have shown a strong link between environmental risk factors and development of MS. Most epidemiologic evidence points toward EBV infection, exposure to cigarette smoke, and vitamin D deficiency as risk factors. EBV infection and cigarette smoking have been studied as risk factors for pediatric MS, noted Dr. Munger.
EBV Infection
Most people become infected with EBV during childhood; however, some individuals contract the virus during adolescence or early adulthood and are more likely to have symptomatic infection that will manifest as infectious mononucleosis. Similarities between the epidemiology of infectious mononucleosis and MS “have prompted investigators to examine whether a history of infectious mononucleosis is associated with MS risk,” Dr. Munger commented.
A meta-analysis published in 2006 found that infectious mononucleosis was associated with a more than twofold increased risk of MS. Since then, three other studies have been published—one in Denmark, one in the Netherlands, and one in Canada. “All three studies also found a greater than twofold increased risk associated with having had infectious mononucleosis,” Dr. Munger noted.
Several other studies have looked at anti-EBV antibodies and risk of MS. These studies have demonstrated a two- to ninefold increased risk of MS with elevated IgG antibodies against Epstein Barr nuclear antigens detected up to 16 to 20 years prior to MS onset.
In a meta-analysis investigating seropositivity for EBV in MS cases, 0.5% of cases were EBV-negative, compared with 6% of controls. “So being EBV-negative is associated with a 94% reduced risk of MS,” said Dr. Munger.
The association between EBV infection and risk of MS has been examined in some pediatric populations, added Dr. Munger. In a Canadian study involving 30 MS cases (mean age of onset, 12) and 90 matched controls, blood samples were collected within 1.5 years after onset of MS. Researchers found that 83% of MS cases had a history of past EBV infection, compared with 42% of controls. “So there was a greater than eightfold increased risk of MS associated with having past EBV infection,” she noted.
In a study conducted in Germany including 147 MS cases (mean age of onset, 12) and 147 matched controls, blood samples were collected an average of one year after onset of MS. More than 80% of children with MS had a history of past EBV infection, compared with 56% of controls. In addition, children with MS had higher antibody titers to viral capsid antigen and Epstein Barr nuclear antigen.
Furthermore, in a study of 96 MS cases and 96 controls from centers in North and South America, Banwell et al demonstrated that more than 80% of cases had evidence of past EBV infection, compared with 60% of controls.
“These studies strengthen the evidence that EBV may have a causal role in MS; however, confirmation in larger studies in additional populations is needed,” stated Dr. Munger.
Exposure to Cigarette Smoke
Cigarette smoking has also been implicated in the development of MS, and findings provide strong motivation for not smoking among individuals at high risk for MS, said Dr. Munger.
In a meta-analysis of prospective studies, ever smoking was associated with a 50% increased risk of MS. In addition, in the Nurses Health Study cohorts, women with one to nine pack-years of smoking had no increased risk of MS, whereas women with 10 to 24 pack-years or 25 or more pack-years of smoking had a 50% to 70% increased risk of MS.
One study of pediatric MS examined whether parental smoking was associated with risk of MS in offspring. A total of 129 confirmed cases of MS with onset before age 16 and 1,038 matched controls were included. Participants were asked if one or both parents smoked within the home before the date of MS onset or before the index date in controls. Findings demonstrated that 62% of MS cases were exposed to parental cigarette smoking, compared with 45% of matched controls. This represented a twofold increased risk of MS in children who were exposed to cigarette smoking. However, these results may be explained by recall or selection bias, she noted.
However, in another study conducted in Sweden, Montgomery et al. found that maternal smoking during pregnancy was not associated with an increased risk of MS in offspring diagnosed with MS before age 16.
Vitamin D Exposure
No studies of vitamin D exposure in pediatric MS have been published, stated Dr. Munger. However, several prospective studies in adults have looked at vitamin D by measuring sun exposure, dietary intake, and levels of serum 25-hydroxyvitamin D [25(OH)D] levels, which are an integrated measure of both sun and dietary sources. Dr. Munger noted that several case-control studies have examined vitamin D exposure in childhood and risk of developing MS as an adult. In one study conducted in Tasmania, Australia, researchers found a 50% to 60% reduced risk of MS with more than four hours of sun exposure between ages 6 and 10. In another study conducted in northern Norway, greater time spent outdoors in the summer between ages 16 and 20 was associated with a 50% reduced risk of MS. In addition, consuming fish—a primary dietary source of vitamin D—more than three times per week was associated with a 50% reduced risk of MS in this cohort. Also, in a study conducted in North America, time spent outdoors in the summer or time spent sun tanning in childhood was associated with a 60% reduced risk of MS.
Because these are case-control studies, “we have to consider that these associations could be explained by recall bias or selection bias,” said Dr. Munger. She also pointed out that another limitation of these studies is that sun exposure is not a direct measure of vitamin D exposure.
The strongest evidence to date that vitamin D may reduce MS risk comes from two prospective studies. The first, among women in the Nurses’ Health Study cohorts, found that women with a dietary intake of at least 400 IU/day of vitamin D had a 40% reduced risk of MS. The main limitation of this study, however, is that diet contributes little to the overall vitamin D nutritional status. Therefore, in the second study, vitamin D exposure was measured by blood levels of 25(OH)D in healthy young adults in the US military. Among whites, levels of 25(OH)D greater than 100 nmol/L were associated with a 50% reduced risk of MS, compared with those with levels less than 75 nmol/L. Whether adequate vitamin D nutrition is associated with a reduced risk of pediatric MS is an important question and one that is currently being studied.
Other Associations With MS Risk
“There have been some other factors in pediatric-onset MS that have been looked at,” said Dr. Munger. In a study conducted in France, researchers assessed the association between hepatitis B vaccination and pediatric-onset MS. An assessment of 143 MS cases with onset before age 16 and 1,122 matched controls showed that neither the timing nor the number of hepatitis B vaccinations was associated with MS risk. However, in a follow-up study, one specific brand of hepatitis B vaccine was associated with a threefold increased risk for MS three years after the last vaccine dose.
In the same population, researchers found that chicken pox appeared to be protective against MS, with 77% of MS cases reporting a history of clinically observed chicken pox, compared with 85% of controls.
Current evidence supports a link between EBV infection and pediatric-onset MS. Studies examining exposure to cigarette smoke and pediatric MS risk are conflicting and more studies are warranted. While there is growing evidence that vitamin D may decrease MS risk among adults, there are currently no studies in pediatric MS. A history of clinically observed chicken pox appears to be protective, and the association between hepatitis B vaccination and pediatric-onset MS remains unclear. However, confirmation of all these findings is needed in larger studies, concluded Dr. Munger.
—Karen L. Spittler
Suggested Reading
Banwell BL. Through the eyes of a child: research insights gained through the study of childhood multiple sclerosis. Mult Scler. 2008;14(1):4-5.
Suggested Reading
Banwell BL. Through the eyes of a child: research insights gained through the study of childhood multiple sclerosis. Mult Scler. 2008;14(1):4-5.