Jeff Evans

The risk for developing Parkinson's disease that is associated with pesticide exposure appears to be especially high in people who are professionally exposed to the chemicals and those who carry certain polymorphisms for glutathione S-transferase genes, according to findings from two new case-control studies.

The studies strengthen the already well-documented association between pesticide exposure and Parkinson's disease (PD) by including a more detailed assessment of exposure to the chemicals for analyzing dose-effect relationships, especially for different classes of insecticides, fungicides, and herbicides, as well as examining the role of genetic traits in determining individual susceptibility to PD.

Dr. Alexis Elbaz of the Institut National de la Santé et de la Recherche Médicale, Paris, and his colleagues conducted extensive in-person interviews about professional exposure to pesticides with 247 patients with PD and 676 matching control patients. All of the participants came from the same French health insurance organization for workers in agriculture and related occupations. The patients with PD had been diagnosed a median of 1.5 years before the study (Ann. Neurol. 2009 [doi:10.1002/ana.21717]).

Dr. Elbaz and his associates found that for men, the odds of developing PD increased with the number of years of professional use of pesticides. This relationship was stronger for men with PD onset after age 65 years than it was for men with younger onset. Women with pesticide exposure also were significantly more likely to develop PD than were those without exposure, the investigators reported.

Of the three broad categories of pesticides that the investigators analyzed—insecticides, fungicides, and herbicides—only insecticide exposure in men was associated with a significantly increased odds of developing PD (odds ratio 2.2). This association followed a dose-effect relationship, which was strongest for older-onset PD patients. In women, only fungicide exposure was associated with significantly increased odds of developing PD (odds ratio 3.5).

In multivariate analyses of men overall and of men with older-onset PD, only organochlorine insecticides remained associated with PD after adjusting for other pesticide families that the men had been exposed to.

During 1941-1990, patients with older-onset PD had used organochlorines in each 10-year period more often than their matched controls had, whereas there was no difference in use during the same periods between patients with younger-onset PD and their matched controls. Each of the control groups used organochlorines, as well as insecticides and pesticides overall, at similar frequencies.

The finding that the association between PD and professional pesticide use was stronger for older males is “consistent with the view that genetic susceptibility plays a stronger role in younger-onset cases, while environmental factors play a stronger role for older-onset cases,” the investigators wrote.

This was supported in the study by a similar number of years of pesticide exposure between both older-onset cases (13 years) and in younger-onset cases (12 years) and a higher cumulative lifetime hours of exposure for younger-onset cases (88 hours), compared with older-onset cases (52 hours).

In a separate study, Dr. Ruey-Meei Wu, of the department of neurology at National Taiwan University Hospital, Taipei, and her coinvestigators genotyped 125 patients (69 women) with sporadic idiopathic PD and 162 age- and gender-matched control patients (90 women) from a rural area of southern Taiwan for four glutathione S-transferase (GST) genes (GSTM1, GSTP1, GSTT1, and GSTZ1).

Overall, 69 PD patients and 70 control patients were exposed to pesticides (herbicides, insecticides, and fungicides) used in professional farming or gardening. These patients had been exposed to pesticides for a range of 1 to 50 years, Dr. Wu and her colleagues reported at a poster session of the International Congress of Parkinson's Disease and Movement Disorders in Paris.

GST polymorphisms have been reported to reduce the efficiency of the substrate selectivity or stability of the enzymes. In brain tissue, GSTs function as scavengers that eliminate the formation of intracellular free radicals that are generated from the metabolism of drugs, toxins such as pesticides, or xenobiotics. GSTs have the potential to modify a person's susceptibility to developing PD after pesticide exposure by increasing oxidative stress in the brain, leading to the degeneration of dopaminergic neurons, Dr. Wu said in an interview.

Pesticide exposure was an independent risk factor for PD. Only the GSTP1 Val 105 polymorphism, which occurred in about 20% of the patients, significantly increased the risk for the development of PD. This polymorphism raised the odds of developing PD by a factor of 2.2. The risk for PD was greatest among patients who had been exposed to pesticides for more than 35 years.

Those who carried the GSTP1 Val 105 polymorphism and were exposed to pesticides had even higher risk of developing PD. There was a trend for increasing PD risk that became stronger and more significant in pesticide-exposed patients who carried an additional putative high-risk GST genotype.

None of the investigators in either study had any conflicts of interest to declare.

The odds of developing Parkinson's disease increased with the number of years of professional use of pesticides. ©LOOK

The risk for developing Parkinson's disease that is associated with pesticide exposure appears to be especially high in people who are professionally exposed to the chemicals and those who carry certain polymorphisms for glutathione S-transferase genes, according to findings from two new case-control studies.

The studies strengthen the already well-documented association between pesticide exposure and Parkinson's disease (PD) by including a more detailed assessment of exposure to the chemicals for analyzing dose-effect relationships, especially for different classes of insecticides, fungicides, and herbicides, as well as examining the role of genetic traits in determining individual susceptibility to PD.

Dr. Alexis Elbaz of the Institut National de la Santé et de la Recherche Médicale, Paris, and his colleagues conducted extensive in-person interviews about professional exposure to pesticides with 247 patients with PD and 676 matching control patients. All of the participants came from the same French health insurance organization for workers in agriculture and related occupations. The patients with PD had been diagnosed a median of 1.5 years before the study (Ann. Neurol. 2009 [doi:10.1002/ana.21717]).

Dr. Elbaz and his associates found that for men, the odds of developing PD increased with the number of years of professional use of pesticides. This relationship was stronger for men with PD onset after age 65 years than it was for men with younger onset. Women with pesticide exposure also were significantly more likely to develop PD than were those without exposure, the investigators reported.

Of the three broad categories of pesticides that the investigators analyzed—insecticides, fungicides, and herbicides—only insecticide exposure in men was associated with a significantly increased odds of developing PD (odds ratio 2.2). This association followed a dose-effect relationship, which was strongest for older-onset PD patients. In women, only fungicide exposure was associated with significantly increased odds of developing PD (odds ratio 3.5).

In multivariate analyses of men overall and of men with older-onset PD, only organochlorine insecticides remained associated with PD after adjusting for other pesticide families that the men had been exposed to.

During 1941-1990, patients with older-onset PD had used organochlorines in each 10-year period more often than their matched controls had, whereas there was no difference in use during the same periods between patients with younger-onset PD and their matched controls. Each of the control groups used organochlorines, as well as insecticides and pesticides overall, at similar frequencies.

The finding that the association between PD and professional pesticide use was stronger for older males is “consistent with the view that genetic susceptibility plays a stronger role in younger-onset cases, while environmental factors play a stronger role for older-onset cases,” the investigators wrote.

This was supported in the study by a similar number of years of pesticide exposure between both older-onset cases (13 years) and in younger-onset cases (12 years) and a higher cumulative lifetime hours of exposure for younger-onset cases (88 hours), compared with older-onset cases (52 hours).

In a separate study, Dr. Ruey-Meei Wu, of the department of neurology at National Taiwan University Hospital, Taipei, and her coinvestigators genotyped 125 patients (69 women) with sporadic idiopathic PD and 162 age- and gender-matched control patients (90 women) from a rural area of southern Taiwan for four glutathione S-transferase (GST) genes (GSTM1, GSTP1, GSTT1, and GSTZ1).

Overall, 69 PD patients and 70 control patients were exposed to pesticides (herbicides, insecticides, and fungicides) used in professional farming or gardening. These patients had been exposed to pesticides for a range of 1 to 50 years, Dr. Wu and her colleagues reported at a poster session of the International Congress of Parkinson's Disease and Movement Disorders in Paris.

GST polymorphisms have been reported to reduce the efficiency of the substrate selectivity or stability of the enzymes. In brain tissue, GSTs function as scavengers that eliminate the formation of intracellular free radicals that are generated from the metabolism of drugs, toxins such as pesticides, or xenobiotics. GSTs have the potential to modify a person's susceptibility to developing PD after pesticide exposure by increasing oxidative stress in the brain, leading to the degeneration of dopaminergic neurons, Dr. Wu said in an interview.

Pesticide exposure was an independent risk factor for PD. Only the GSTP1 Val 105 polymorphism, which occurred in about 20% of the patients, significantly increased the risk for the development of PD. This polymorphism raised the odds of developing PD by a factor of 2.2. The risk for PD was greatest among patients who had been exposed to pesticides for more than 35 years.

Those who carried the GSTP1 Val 105 polymorphism and were exposed to pesticides had even higher risk of developing PD. There was a trend for increasing PD risk that became stronger and more significant in pesticide-exposed patients who carried an additional putative high-risk GST genotype.

None of the investigators in either study had any conflicts of interest to declare.

The odds of developing Parkinson's disease increased with the number of years of professional use of pesticides. ©LOOK

The risk for developing Parkinson's disease that is associated with pesticide exposure appears to be especially high in people who are professionally exposed to the chemicals and those who carry certain polymorphisms for glutathione S-transferase genes, according to findings from two new case-control studies.

The studies strengthen the already well-documented association between pesticide exposure and Parkinson's disease (PD) by including a more detailed assessment of exposure to the chemicals for analyzing dose-effect relationships, especially for different classes of insecticides, fungicides, and herbicides, as well as examining the role of genetic traits in determining individual susceptibility to PD.

Dr. Alexis Elbaz of the Institut National de la Santé et de la Recherche Médicale, Paris, and his colleagues conducted extensive in-person interviews about professional exposure to pesticides with 247 patients with PD and 676 matching control patients. All of the participants came from the same French health insurance organization for workers in agriculture and related occupations. The patients with PD had been diagnosed a median of 1.5 years before the study (Ann. Neurol. 2009 [doi:10.1002/ana.21717]).

Dr. Elbaz and his associates found that for men, the odds of developing PD increased with the number of years of professional use of pesticides. This relationship was stronger for men with PD onset after age 65 years than it was for men with younger onset. Women with pesticide exposure also were significantly more likely to develop PD than were those without exposure, the investigators reported.

Of the three broad categories of pesticides that the investigators analyzed—insecticides, fungicides, and herbicides—only insecticide exposure in men was associated with a significantly increased odds of developing PD (odds ratio 2.2). This association followed a dose-effect relationship, which was strongest for older-onset PD patients. In women, only fungicide exposure was associated with significantly increased odds of developing PD (odds ratio 3.5).

In multivariate analyses of men overall and of men with older-onset PD, only organochlorine insecticides remained associated with PD after adjusting for other pesticide families that the men had been exposed to.

During 1941-1990, patients with older-onset PD had used organochlorines in each 10-year period more often than their matched controls had, whereas there was no difference in use during the same periods between patients with younger-onset PD and their matched controls. Each of the control groups used organochlorines, as well as insecticides and pesticides overall, at similar frequencies.

The finding that the association between PD and professional pesticide use was stronger for older males is “consistent with the view that genetic susceptibility plays a stronger role in younger-onset cases, while environmental factors play a stronger role for older-onset cases,” the investigators wrote.

This was supported in the study by a similar number of years of pesticide exposure between both older-onset cases (13 years) and in younger-onset cases (12 years) and a higher cumulative lifetime hours of exposure for younger-onset cases (88 hours), compared with older-onset cases (52 hours).

In a separate study, Dr. Ruey-Meei Wu, of the department of neurology at National Taiwan University Hospital, Taipei, and her coinvestigators genotyped 125 patients (69 women) with sporadic idiopathic PD and 162 age- and gender-matched control patients (90 women) from a rural area of southern Taiwan for four glutathione S-transferase (GST) genes (GSTM1, GSTP1, GSTT1, and GSTZ1).

Overall, 69 PD patients and 70 control patients were exposed to pesticides (herbicides, insecticides, and fungicides) used in professional farming or gardening. These patients had been exposed to pesticides for a range of 1 to 50 years, Dr. Wu and her colleagues reported at a poster session of the International Congress of Parkinson's Disease and Movement Disorders in Paris.

GST polymorphisms have been reported to reduce the efficiency of the substrate selectivity or stability of the enzymes. In brain tissue, GSTs function as scavengers that eliminate the formation of intracellular free radicals that are generated from the metabolism of drugs, toxins such as pesticides, or xenobiotics. GSTs have the potential to modify a person's susceptibility to developing PD after pesticide exposure by increasing oxidative stress in the brain, leading to the degeneration of dopaminergic neurons, Dr. Wu said in an interview.

Pesticide exposure was an independent risk factor for PD. Only the GSTP1 Val 105 polymorphism, which occurred in about 20% of the patients, significantly increased the risk for the development of PD. This polymorphism raised the odds of developing PD by a factor of 2.2. The risk for PD was greatest among patients who had been exposed to pesticides for more than 35 years.

Those who carried the GSTP1 Val 105 polymorphism and were exposed to pesticides had even higher risk of developing PD. There was a trend for increasing PD risk that became stronger and more significant in pesticide-exposed patients who carried an additional putative high-risk GST genotype.

None of the investigators in either study had any conflicts of interest to declare.

The odds of developing Parkinson's disease increased with the number of years of professional use of pesticides. ©LOOK

WASHINGTON — The potential health threat of environmental exposure to endocrine-disrupting chemicals such as bisphenol A has become a top concern of the Endocrine Society, which issued its first scientific statement on the substances last month.

“There was no question about whether to prioritize endocrine-disrupting compounds as a No. 1 issue to explore above many other issues that were competing that have major public health implications,” Dr. Robert M. Carey, president of the Endocrine Society, said at a press briefing at the society's annual meeting. “Science has taken us up to a point where we are concerned.”

Researchers also presented animal studies of the possible effects of bisphenol A (BPA) on cardiac arrhythmias and epigenetic imprinting during gestation, as well as the possible continual exposure of most of the U.S. population to levels of the substance at 20 times the Environmental Protection Agency's accepted safe daily intake (50 mcg/kg).

The scientific statement is the “consensus of the best scientists in the world” in summarizing evidence on the effects of endocrine-disrupting chemicals (EDCs) and in identifying basic and clinical research knowledge gaps. “Obviously we don't know all the answers—far from it—for EDCs, so this is extremely important,” said Dr. Carey, noting that the EPA announced in April that it will require pesticide manufacturers to test 67 chemicals in their products to determine whether they disrupt the endocrine system.

“We present evidence that endocrine disruptors do have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid disease, metabolism and obesity, and … cardiovascular endocrinology,” Dr. Carey said.

EDCs noted in the review include environmental estrogens, or estrogen mimics, most notably BPA—a synthetic monomer that is used in the production of polycarbonate plastics and epoxy resins—as well as polychlorinated biphenyls, diethylstilbestrol, dioxins, and phthalates. Other EDCs identified in the report include antiandrogen substances such as the fungicide vinclozolin and the insecticide DDT and its metabolic derivative DDE (Endocr. Rev. 2009;30:293-342).

In light of the findings highlighted in the review, the authors advised several courses of action to address in clinical practice. Clinicians should become educated about the sources and effects of environmental contaminant exposures in utero and across the life span, and should take a careful history of the onset of reproductive disorders along with an occupational and environmental exposure history, according to the statement. Clinicians also can advise patients about minimizing their risks of exposure.

Dr. Hugh Taylor said that he tells his patients to “avoid things that we know have a high level of bisphenol A,” such as hard plastic water bottles and canned goods. This will help to lower BPA levels “until we start to see it taken out of all the things that we are not even aware of that we are exposed to every day.”

Dr. Taylor reported a study in which he and his colleagues found that offspring of pregnant mice that had been injected with 5 mg/kg of BPA per day for a week had epigenetic changes in the methylation pattern of a gene involved in the uterine development. This altered methylation pattern, which was not seen in the offspring of control mice, resulted in a permanent increase in estrogen sensitivity, said Dr. Taylor, professor of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.

Other research, presented by Scott Belcher, Ph.D., of the University of Cincinnati, showed that BPA at nanomolar doses can act alone or in combination with estrogen to increase arrhythmic pulsing of ventricular cardiomyocytes from female rats and mice, as well as to increase the frequency of arrhythmias in whole hearts of female rats and mice.

A well-known researcher of BPA toxicology, Frederick vom Saal, Ph.D., of the University of Missouri, Columbia, also reported a study at the press briefing. He and his colleagues found that an orally administered dose of 400 mg/kg BPA is continually excreted and does not accumulate in the body of female rhesus macaques, a good model for human metabolism of chemicals such as BPA.

But the researchers found that the levels of biologically active BPA over a 24-hour period never dropped below average levels of the chemical that are found in people in the United States and other developed countries, suggesting that people are exposed to even higher levels. For people to have such high levels, they must be exposed to BPA from many unknown sources, Dr. vom Saal said, noting that 8-9 billion pounds of BPA are used in products worldwide each year.

Dr. Taylor argued that “we're not going to find unexposed human populations” to compare with exposed groups. “The human experiment will never be done [and] we can't afford to wait until we have perfect data in humans.

“When we see associations in humans mimicking exactly what we've proven are cause and effect in animals, I think that's pretty compelling,” he added.

The National Institutes of Health funded the BPA studies and the scientific statement. Additional funding for the statement came from the European Commission, the Belgian Study Group for Pediatric Endocrinology, and grants from the Belgian Fonds de la Recherche Scientific Médicale. One author reported that he has served on the EPA advisory board, has received honoraria for university lectures, and has served as an expert witness in federal court.

A related video is at www.youtube.com/InternalMedicineNews

WASHINGTON — The potential health threat of environmental exposure to endocrine-disrupting chemicals such as bisphenol A has become a top concern of the Endocrine Society, which issued its first scientific statement on the substances last month.

“There was no question about whether to prioritize endocrine-disrupting compounds as a No. 1 issue to explore above many other issues that were competing that have major public health implications,” Dr. Robert M. Carey, president of the Endocrine Society, said at a press briefing at the society's annual meeting. “Science has taken us up to a point where we are concerned.”

Researchers also presented animal studies of the possible effects of bisphenol A (BPA) on cardiac arrhythmias and epigenetic imprinting during gestation, as well as the possible continual exposure of most of the U.S. population to levels of the substance at 20 times the Environmental Protection Agency's accepted safe daily intake (50 mcg/kg).

The scientific statement is the “consensus of the best scientists in the world” in summarizing evidence on the effects of endocrine-disrupting chemicals (EDCs) and in identifying basic and clinical research knowledge gaps. “Obviously we don't know all the answers—far from it—for EDCs, so this is extremely important,” said Dr. Carey, noting that the EPA announced in April that it will require pesticide manufacturers to test 67 chemicals in their products to determine whether they disrupt the endocrine system.

“We present evidence that endocrine disruptors do have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid disease, metabolism and obesity, and … cardiovascular endocrinology,” Dr. Carey said.

EDCs noted in the review include environmental estrogens, or estrogen mimics, most notably BPA—a synthetic monomer that is used in the production of polycarbonate plastics and epoxy resins—as well as polychlorinated biphenyls, diethylstilbestrol, dioxins, and phthalates. Other EDCs identified in the report include antiandrogen substances such as the fungicide vinclozolin and the insecticide DDT and its metabolic derivative DDE (Endocr. Rev. 2009;30:293-342).

In light of the findings highlighted in the review, the authors advised several courses of action to address in clinical practice. Clinicians should become educated about the sources and effects of environmental contaminant exposures in utero and across the life span, and should take a careful history of the onset of reproductive disorders along with an occupational and environmental exposure history, according to the statement. Clinicians also can advise patients about minimizing their risks of exposure.

Dr. Hugh Taylor said that he tells his patients to “avoid things that we know have a high level of bisphenol A,” such as hard plastic water bottles and canned goods. This will help to lower BPA levels “until we start to see it taken out of all the things that we are not even aware of that we are exposed to every day.”

Dr. Taylor reported a study in which he and his colleagues found that offspring of pregnant mice that had been injected with 5 mg/kg of BPA per day for a week had epigenetic changes in the methylation pattern of a gene involved in the uterine development. This altered methylation pattern, which was not seen in the offspring of control mice, resulted in a permanent increase in estrogen sensitivity, said Dr. Taylor, professor of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.

Other research, presented by Scott Belcher, Ph.D., of the University of Cincinnati, showed that BPA at nanomolar doses can act alone or in combination with estrogen to increase arrhythmic pulsing of ventricular cardiomyocytes from female rats and mice, as well as to increase the frequency of arrhythmias in whole hearts of female rats and mice.

A well-known researcher of BPA toxicology, Frederick vom Saal, Ph.D., of the University of Missouri, Columbia, also reported a study at the press briefing. He and his colleagues found that an orally administered dose of 400 mg/kg BPA is continually excreted and does not accumulate in the body of female rhesus macaques, a good model for human metabolism of chemicals such as BPA.

But the researchers found that the levels of biologically active BPA over a 24-hour period never dropped below average levels of the chemical that are found in people in the United States and other developed countries, suggesting that people are exposed to even higher levels. For people to have such high levels, they must be exposed to BPA from many unknown sources, Dr. vom Saal said, noting that 8-9 billion pounds of BPA are used in products worldwide each year.

Dr. Taylor argued that “we're not going to find unexposed human populations” to compare with exposed groups. “The human experiment will never be done [and] we can't afford to wait until we have perfect data in humans.

“When we see associations in humans mimicking exactly what we've proven are cause and effect in animals, I think that's pretty compelling,” he added.

The National Institutes of Health funded the BPA studies and the scientific statement. Additional funding for the statement came from the European Commission, the Belgian Study Group for Pediatric Endocrinology, and grants from the Belgian Fonds de la Recherche Scientific Médicale. One author reported that he has served on the EPA advisory board, has received honoraria for university lectures, and has served as an expert witness in federal court.

A related video is at www.youtube.com/InternalMedicineNews

WASHINGTON — The potential health threat of environmental exposure to endocrine-disrupting chemicals such as bisphenol A has become a top concern of the Endocrine Society, which issued its first scientific statement on the substances last month.

“There was no question about whether to prioritize endocrine-disrupting compounds as a No. 1 issue to explore above many other issues that were competing that have major public health implications,” Dr. Robert M. Carey, president of the Endocrine Society, said at a press briefing at the society's annual meeting. “Science has taken us up to a point where we are concerned.”

Researchers also presented animal studies of the possible effects of bisphenol A (BPA) on cardiac arrhythmias and epigenetic imprinting during gestation, as well as the possible continual exposure of most of the U.S. population to levels of the substance at 20 times the Environmental Protection Agency's accepted safe daily intake (50 mcg/kg).

The scientific statement is the “consensus of the best scientists in the world” in summarizing evidence on the effects of endocrine-disrupting chemicals (EDCs) and in identifying basic and clinical research knowledge gaps. “Obviously we don't know all the answers—far from it—for EDCs, so this is extremely important,” said Dr. Carey, noting that the EPA announced in April that it will require pesticide manufacturers to test 67 chemicals in their products to determine whether they disrupt the endocrine system.

“We present evidence that endocrine disruptors do have effects on male and female reproduction, breast development and cancer, prostate cancer, neuroendocrinology, thyroid disease, metabolism and obesity, and … cardiovascular endocrinology,” Dr. Carey said.

EDCs noted in the review include environmental estrogens, or estrogen mimics, most notably BPA—a synthetic monomer that is used in the production of polycarbonate plastics and epoxy resins—as well as polychlorinated biphenyls, diethylstilbestrol, dioxins, and phthalates. Other EDCs identified in the report include antiandrogen substances such as the fungicide vinclozolin and the insecticide DDT and its metabolic derivative DDE (Endocr. Rev. 2009;30:293-342).

In light of the findings highlighted in the review, the authors advised several courses of action to address in clinical practice. Clinicians should become educated about the sources and effects of environmental contaminant exposures in utero and across the life span, and should take a careful history of the onset of reproductive disorders along with an occupational and environmental exposure history, according to the statement. Clinicians also can advise patients about minimizing their risks of exposure.

Dr. Hugh Taylor said that he tells his patients to “avoid things that we know have a high level of bisphenol A,” such as hard plastic water bottles and canned goods. This will help to lower BPA levels “until we start to see it taken out of all the things that we are not even aware of that we are exposed to every day.”

Dr. Taylor reported a study in which he and his colleagues found that offspring of pregnant mice that had been injected with 5 mg/kg of BPA per day for a week had epigenetic changes in the methylation pattern of a gene involved in the uterine development. This altered methylation pattern, which was not seen in the offspring of control mice, resulted in a permanent increase in estrogen sensitivity, said Dr. Taylor, professor of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.

Other research, presented by Scott Belcher, Ph.D., of the University of Cincinnati, showed that BPA at nanomolar doses can act alone or in combination with estrogen to increase arrhythmic pulsing of ventricular cardiomyocytes from female rats and mice, as well as to increase the frequency of arrhythmias in whole hearts of female rats and mice.

A well-known researcher of BPA toxicology, Frederick vom Saal, Ph.D., of the University of Missouri, Columbia, also reported a study at the press briefing. He and his colleagues found that an orally administered dose of 400 mg/kg BPA is continually excreted and does not accumulate in the body of female rhesus macaques, a good model for human metabolism of chemicals such as BPA.

But the researchers found that the levels of biologically active BPA over a 24-hour period never dropped below average levels of the chemical that are found in people in the United States and other developed countries, suggesting that people are exposed to even higher levels. For people to have such high levels, they must be exposed to BPA from many unknown sources, Dr. vom Saal said, noting that 8-9 billion pounds of BPA are used in products worldwide each year.

Dr. Taylor argued that “we're not going to find unexposed human populations” to compare with exposed groups. “The human experiment will never be done [and] we can't afford to wait until we have perfect data in humans.

“When we see associations in humans mimicking exactly what we've proven are cause and effect in animals, I think that's pretty compelling,” he added.

The National Institutes of Health funded the BPA studies and the scientific statement. Additional funding for the statement came from the European Commission, the Belgian Study Group for Pediatric Endocrinology, and grants from the Belgian Fonds de la Recherche Scientific Médicale. One author reported that he has served on the EPA advisory board, has received honoraria for university lectures, and has served as an expert witness in federal court.

A related video is at www.youtube.com/InternalMedicineNews

SEATTLE — Reductions in skin elasticity appear to be a possible biomarker for the progression of amyotrophic lateral sclerosis that deserves further study, according to study results.

The change in the potential biomarker was associated with changes in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and other clinical measures of disease progression, including forced vital capacity.

ALS patients are known to have reduced skin elasticity, in which the skin returns slowly to its original shape and dimensions after being stretched. However, this phenomenon has not been quantified and suffers from substantial intra- and interobserver variability.

Structural and biochemical abnormalities of the skin in ALS also have been identified, including reduced and loosely woven collagen bundles with accumulation of amorphous materials between the bundles, collagen fibrils with irregular diameter, noninflammatory vasculopathy, and deposits of beta-amyloid protein close to blood vessels. One study also found a significant negative correlation between the diameter of collagen fibrils and the duration of ALS (J. Neurol. Sci. 1993;119:74-8), Dr. Harvey Arbesman said at the annual meeting of the American Academy of Neurology.

The skin changes that appear in ALS patients could be analogous to changes that are occurring in the CNS because both the CNS and skin arise from the neural crest in development and many diseases affect both systems, suggested Dr. Arbesman, a dermatologist in Williamsville, N.Y.

"Our objective was to test the hypothesis that chronologic, quantitative measurements of skin elasticity could be a useful, noninvasive, biomechanical biomarker of disease progression in patients with ALS and aid in diagnosis," he said.

Dr. Arbesman and his colleagues measured skin elasticity with a cutometer on the arm and back at baseline in 40 ALS patients and 30 of their family members or caregivers, who served as controls. Most of the control participants were spouses. None of the patients had superoxide dismutase 1 (SOD1) mutations, which are known to cause about 20% of familial ALS cases.

Compared with the controls, skin elasticity in ALS patients was significantly reduced in measurements on the arm with 2-mm and 8-mm Cutometer probes.

The investigators controlled for age at baseline because skin elasticity declines with age. Cutometer measurements with 2-mm probes assessed the elastic properties of the epidermis and papillary dermis, whereas measurements with the 8-mm probe evaluated the elastic properties of the whole skin, he said.

"We took into account if the patient had developed, let's say, right-sided disease first and that was the presenting complaint, then we used the affected side. If it was bilateral involvement when it was presented, then by default we used the right side," Dr. Arbesman said.

Because the hydration status of the skin will affect its elasticity, the investigators instructed patients not to make any changes in their skin care habits on the day of each visit. The air temperature and humidity of the clinic were monitored at each visit to ensure that they were the same.

Skin elasticity on the back was significantly correlated with scores on the ALS Functional Rating Scale-Revised, as well as forced vital capacity, at 3 months. The group has collected 6-month follow-up data that are still being analyzed, he said.

The changes in the Cutometer readings between baseline and follow-up measurements were assessed on a plot of the area under the curve for the ratio between the two curves that are generated during the suction and relaxation phases of the elasticity measurement for each anatomic location. This tends to correct for any edema or changes in subcutaneous fat that might have occurred between measurements, he said.

"Further studies are needed to elucidate the relationship of this biomarker to specific biochemical changes relevant to the pathogenesis of ALS," Dr. Arbesman concluded.

The study was funded by ArbesIdeas Inc., the Muscular Dystrophy Association's Wings Over Wall Street, Prize4Life, and the University of Missouri-Columbia Dermatology Research Fund. Dr. Arbesman, the vice president of ArbesIdeas Inc., was awarded part of a $100,000 prize pool for winning Prize4Life's ALS Biomarker Discovery Prize.

SEATTLE — Reductions in skin elasticity appear to be a possible biomarker for the progression of amyotrophic lateral sclerosis that deserves further study, according to study results.

The change in the potential biomarker was associated with changes in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and other clinical measures of disease progression, including forced vital capacity.

ALS patients are known to have reduced skin elasticity, in which the skin returns slowly to its original shape and dimensions after being stretched. However, this phenomenon has not been quantified and suffers from substantial intra- and interobserver variability.

Structural and biochemical abnormalities of the skin in ALS also have been identified, including reduced and loosely woven collagen bundles with accumulation of amorphous materials between the bundles, collagen fibrils with irregular diameter, noninflammatory vasculopathy, and deposits of beta-amyloid protein close to blood vessels. One study also found a significant negative correlation between the diameter of collagen fibrils and the duration of ALS (J. Neurol. Sci. 1993;119:74-8), Dr. Harvey Arbesman said at the annual meeting of the American Academy of Neurology.

The skin changes that appear in ALS patients could be analogous to changes that are occurring in the CNS because both the CNS and skin arise from the neural crest in development and many diseases affect both systems, suggested Dr. Arbesman, a dermatologist in Williamsville, N.Y.

"Our objective was to test the hypothesis that chronologic, quantitative measurements of skin elasticity could be a useful, noninvasive, biomechanical biomarker of disease progression in patients with ALS and aid in diagnosis," he said.

Dr. Arbesman and his colleagues measured skin elasticity with a cutometer on the arm and back at baseline in 40 ALS patients and 30 of their family members or caregivers, who served as controls. Most of the control participants were spouses. None of the patients had superoxide dismutase 1 (SOD1) mutations, which are known to cause about 20% of familial ALS cases.

Compared with the controls, skin elasticity in ALS patients was significantly reduced in measurements on the arm with 2-mm and 8-mm Cutometer probes.

The investigators controlled for age at baseline because skin elasticity declines with age. Cutometer measurements with 2-mm probes assessed the elastic properties of the epidermis and papillary dermis, whereas measurements with the 8-mm probe evaluated the elastic properties of the whole skin, he said.

"We took into account if the patient had developed, let's say, right-sided disease first and that was the presenting complaint, then we used the affected side. If it was bilateral involvement when it was presented, then by default we used the right side," Dr. Arbesman said.

Because the hydration status of the skin will affect its elasticity, the investigators instructed patients not to make any changes in their skin care habits on the day of each visit. The air temperature and humidity of the clinic were monitored at each visit to ensure that they were the same.

Skin elasticity on the back was significantly correlated with scores on the ALS Functional Rating Scale-Revised, as well as forced vital capacity, at 3 months. The group has collected 6-month follow-up data that are still being analyzed, he said.

The changes in the Cutometer readings between baseline and follow-up measurements were assessed on a plot of the area under the curve for the ratio between the two curves that are generated during the suction and relaxation phases of the elasticity measurement for each anatomic location. This tends to correct for any edema or changes in subcutaneous fat that might have occurred between measurements, he said.

"Further studies are needed to elucidate the relationship of this biomarker to specific biochemical changes relevant to the pathogenesis of ALS," Dr. Arbesman concluded.

The study was funded by ArbesIdeas Inc., the Muscular Dystrophy Association's Wings Over Wall Street, Prize4Life, and the University of Missouri-Columbia Dermatology Research Fund. Dr. Arbesman, the vice president of ArbesIdeas Inc., was awarded part of a $100,000 prize pool for winning Prize4Life's ALS Biomarker Discovery Prize.

SEATTLE — Reductions in skin elasticity appear to be a possible biomarker for the progression of amyotrophic lateral sclerosis that deserves further study, according to study results.

The change in the potential biomarker was associated with changes in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised and other clinical measures of disease progression, including forced vital capacity.

ALS patients are known to have reduced skin elasticity, in which the skin returns slowly to its original shape and dimensions after being stretched. However, this phenomenon has not been quantified and suffers from substantial intra- and interobserver variability.

Structural and biochemical abnormalities of the skin in ALS also have been identified, including reduced and loosely woven collagen bundles with accumulation of amorphous materials between the bundles, collagen fibrils with irregular diameter, noninflammatory vasculopathy, and deposits of beta-amyloid protein close to blood vessels. One study also found a significant negative correlation between the diameter of collagen fibrils and the duration of ALS (J. Neurol. Sci. 1993;119:74-8), Dr. Harvey Arbesman said at the annual meeting of the American Academy of Neurology.

The skin changes that appear in ALS patients could be analogous to changes that are occurring in the CNS because both the CNS and skin arise from the neural crest in development and many diseases affect both systems, suggested Dr. Arbesman, a dermatologist in Williamsville, N.Y.

"Our objective was to test the hypothesis that chronologic, quantitative measurements of skin elasticity could be a useful, noninvasive, biomechanical biomarker of disease progression in patients with ALS and aid in diagnosis," he said.

Dr. Arbesman and his colleagues measured skin elasticity with a cutometer on the arm and back at baseline in 40 ALS patients and 30 of their family members or caregivers, who served as controls. Most of the control participants were spouses. None of the patients had superoxide dismutase 1 (SOD1) mutations, which are known to cause about 20% of familial ALS cases.

Compared with the controls, skin elasticity in ALS patients was significantly reduced in measurements on the arm with 2-mm and 8-mm Cutometer probes.

The investigators controlled for age at baseline because skin elasticity declines with age. Cutometer measurements with 2-mm probes assessed the elastic properties of the epidermis and papillary dermis, whereas measurements with the 8-mm probe evaluated the elastic properties of the whole skin, he said.

"We took into account if the patient had developed, let's say, right-sided disease first and that was the presenting complaint, then we used the affected side. If it was bilateral involvement when it was presented, then by default we used the right side," Dr. Arbesman said.

Because the hydration status of the skin will affect its elasticity, the investigators instructed patients not to make any changes in their skin care habits on the day of each visit. The air temperature and humidity of the clinic were monitored at each visit to ensure that they were the same.

Skin elasticity on the back was significantly correlated with scores on the ALS Functional Rating Scale-Revised, as well as forced vital capacity, at 3 months. The group has collected 6-month follow-up data that are still being analyzed, he said.

The changes in the Cutometer readings between baseline and follow-up measurements were assessed on a plot of the area under the curve for the ratio between the two curves that are generated during the suction and relaxation phases of the elasticity measurement for each anatomic location. This tends to correct for any edema or changes in subcutaneous fat that might have occurred between measurements, he said.

"Further studies are needed to elucidate the relationship of this biomarker to specific biochemical changes relevant to the pathogenesis of ALS," Dr. Arbesman concluded.

The study was funded by ArbesIdeas Inc., the Muscular Dystrophy Association's Wings Over Wall Street, Prize4Life, and the University of Missouri-Columbia Dermatology Research Fund. Dr. Arbesman, the vice president of ArbesIdeas Inc., was awarded part of a $100,000 prize pool for winning Prize4Life's ALS Biomarker Discovery Prize.

WASHINGTON — Psychogenic movement disorders could be classified with greater simplicity and possibly diagnosed with greater accuracy in a system that expands the ways in which patients can meet criteria for the disorders, according to Dr. Anthony E. Lang.

The original classification scheme for psychogenic movement disorders (PMDs) proposed by Dr. Stanley Fahn and Dr. Daniel Williams (Adv. Neurol. 1988;50:431-55) subdivided the diagnosis based on the level of diagnostic certainty. The original two categories of “documented” and “clinically established” later merged to become clinically definite PMD (Adv. Neurol. 1995;65:231-57), which are “the majority that we see in the clinics,” said Dr. Lang, professor of neurology at the University of Toronto. Other cases were classified as “probable” or “possible.”

But the Fahn and Williams classification scheme does not take into account the ability to confirm the diagnosis as psychogenic using electrophysiologic testing, Dr. Lang said at an international conference sponsored by the Movement Disorder Society.

Dr. Lang proposed revising the classification scheme to define “clinically definite” PMD as documented, clinically established plus other features (false neurologic signs or psychiatric problems), or clinically established without other features. A “laboratory-supported” definite PMD diagnosis would be made on evidence from electrophysiologic testing. “Possible” PMD could define a movement disorder that has either clinical or electrophysiologic characteristics that are suggestive of a psychogenic condition but leave room for doubt, such as patients with combined psychogenic and organic movement disorders or with organic movement disorders that have superimposed psychogenic features.

The Fahn and Williams classification system, which is the one most commonly used in research and clinical practice, also cannot accurately classify patients who have clinically unequivocal psychogenic features based on distractibility or entrainment but lack false neurologic signs or multiple somatizations that are required for a clinically established PMD diagnosis; they can only be diagnosed as probable although they meet all the clinical criteria for a “nonorganic” movement disorder, he said.

The classification system insists that probable or possible PMD can be diagnosed with patients who have movement disorders that are consistent and congruent with an organic counterpart, but many of those patients may have an organic movement disorder with a great deal of functional overlay or a combination of organic and nonorganic movement disorders, Dr. Lang said.

“It's very common to see patients with mixed [movements]. They may have some bizarre movement disorder or a phenotype that's difficult to classify but then also have a prominent tremor or dystonia,” he said.

“Certain clinical phenotypes strongly suggest a PMD, although this is a somewhat controversial area, Dr. Lang said. These include tremors that never vary in amplitude in rest, postural, and action states and certain types of leg tremor, such as prominent thigh tremors.

In addition, certain dystonic postures are characteristic of PMDs. A lack of arm swing in a patient with hemiparkinsonism may be characteristic of a PMD.

A revision of the Fahn and Williams scheme might lead to more precise diagnoses of PMDs. DR. LANG

WASHINGTON — Psychogenic movement disorders could be classified with greater simplicity and possibly diagnosed with greater accuracy in a system that expands the ways in which patients can meet criteria for the disorders, according to Dr. Anthony E. Lang.

The original classification scheme for psychogenic movement disorders (PMDs) proposed by Dr. Stanley Fahn and Dr. Daniel Williams (Adv. Neurol. 1988;50:431-55) subdivided the diagnosis based on the level of diagnostic certainty. The original two categories of “documented” and “clinically established” later merged to become clinically definite PMD (Adv. Neurol. 1995;65:231-57), which are “the majority that we see in the clinics,” said Dr. Lang, professor of neurology at the University of Toronto. Other cases were classified as “probable” or “possible.”

But the Fahn and Williams classification scheme does not take into account the ability to confirm the diagnosis as psychogenic using electrophysiologic testing, Dr. Lang said at an international conference sponsored by the Movement Disorder Society.

Dr. Lang proposed revising the classification scheme to define “clinically definite” PMD as documented, clinically established plus other features (false neurologic signs or psychiatric problems), or clinically established without other features. A “laboratory-supported” definite PMD diagnosis would be made on evidence from electrophysiologic testing. “Possible” PMD could define a movement disorder that has either clinical or electrophysiologic characteristics that are suggestive of a psychogenic condition but leave room for doubt, such as patients with combined psychogenic and organic movement disorders or with organic movement disorders that have superimposed psychogenic features.

The Fahn and Williams classification system, which is the one most commonly used in research and clinical practice, also cannot accurately classify patients who have clinically unequivocal psychogenic features based on distractibility or entrainment but lack false neurologic signs or multiple somatizations that are required for a clinically established PMD diagnosis; they can only be diagnosed as probable although they meet all the clinical criteria for a “nonorganic” movement disorder, he said.

The classification system insists that probable or possible PMD can be diagnosed with patients who have movement disorders that are consistent and congruent with an organic counterpart, but many of those patients may have an organic movement disorder with a great deal of functional overlay or a combination of organic and nonorganic movement disorders, Dr. Lang said.

“It's very common to see patients with mixed [movements]. They may have some bizarre movement disorder or a phenotype that's difficult to classify but then also have a prominent tremor or dystonia,” he said.

“Certain clinical phenotypes strongly suggest a PMD, although this is a somewhat controversial area, Dr. Lang said. These include tremors that never vary in amplitude in rest, postural, and action states and certain types of leg tremor, such as prominent thigh tremors.

In addition, certain dystonic postures are characteristic of PMDs. A lack of arm swing in a patient with hemiparkinsonism may be characteristic of a PMD.

A revision of the Fahn and Williams scheme might lead to more precise diagnoses of PMDs. DR. LANG

WASHINGTON — Psychogenic movement disorders could be classified with greater simplicity and possibly diagnosed with greater accuracy in a system that expands the ways in which patients can meet criteria for the disorders, according to Dr. Anthony E. Lang.

The original classification scheme for psychogenic movement disorders (PMDs) proposed by Dr. Stanley Fahn and Dr. Daniel Williams (Adv. Neurol. 1988;50:431-55) subdivided the diagnosis based on the level of diagnostic certainty. The original two categories of “documented” and “clinically established” later merged to become clinically definite PMD (Adv. Neurol. 1995;65:231-57), which are “the majority that we see in the clinics,” said Dr. Lang, professor of neurology at the University of Toronto. Other cases were classified as “probable” or “possible.”

But the Fahn and Williams classification scheme does not take into account the ability to confirm the diagnosis as psychogenic using electrophysiologic testing, Dr. Lang said at an international conference sponsored by the Movement Disorder Society.

Dr. Lang proposed revising the classification scheme to define “clinically definite” PMD as documented, clinically established plus other features (false neurologic signs or psychiatric problems), or clinically established without other features. A “laboratory-supported” definite PMD diagnosis would be made on evidence from electrophysiologic testing. “Possible” PMD could define a movement disorder that has either clinical or electrophysiologic characteristics that are suggestive of a psychogenic condition but leave room for doubt, such as patients with combined psychogenic and organic movement disorders or with organic movement disorders that have superimposed psychogenic features.

The Fahn and Williams classification system, which is the one most commonly used in research and clinical practice, also cannot accurately classify patients who have clinically unequivocal psychogenic features based on distractibility or entrainment but lack false neurologic signs or multiple somatizations that are required for a clinically established PMD diagnosis; they can only be diagnosed as probable although they meet all the clinical criteria for a “nonorganic” movement disorder, he said.

The classification system insists that probable or possible PMD can be diagnosed with patients who have movement disorders that are consistent and congruent with an organic counterpart, but many of those patients may have an organic movement disorder with a great deal of functional overlay or a combination of organic and nonorganic movement disorders, Dr. Lang said.

“It's very common to see patients with mixed [movements]. They may have some bizarre movement disorder or a phenotype that's difficult to classify but then also have a prominent tremor or dystonia,” he said.

“Certain clinical phenotypes strongly suggest a PMD, although this is a somewhat controversial area, Dr. Lang said. These include tremors that never vary in amplitude in rest, postural, and action states and certain types of leg tremor, such as prominent thigh tremors.

In addition, certain dystonic postures are characteristic of PMDs. A lack of arm swing in a patient with hemiparkinsonism may be characteristic of a PMD.

A revision of the Fahn and Williams scheme might lead to more precise diagnoses of PMDs. DR. LANG

WASHINGTON – Psychogenic movement disorders could be classified with greater simplicity and possibly diagnosed with greater accuracy in a system that expands the ways in which patients can meet criteria for the disorders, according to Dr. Anthony E. Lang.

The original classification scheme for psychogenic movement disorders (PMDs) proposed by Dr. Stanley Fahn and Dr. Daniel Williams (Adv. Neurol. 1988;50:431-55) subdivided the diagnosis based on the level of diagnostic certainty. The original two categories of “documented” and “clinically established” later merged to become clinically definite PMD (Adv. Neurol. 1995;65:231-57), which are “the majority that we see in the clinics,” said Dr. Lang, professor of neurology at the University of Toronto. Other cases were classified as “probable” or “possible.”

But the Fahn and Williams classification scheme does not take into account the ability to confirm the diagnosis as psychogenic using electrophysiologic testing, Dr. Lang said at an international conference sponsored by the Movement Disorder Society.

Dr. Lang proposed revising the classification scheme to define “clinically definite” PMD as documented, clinically established plus other features (false neurologic signs or psychiatric problems), or clinically established without other features. A “laboratory-supported” definite PMD diagnosis would be made on evidence from electrophysiologic testing. “Possible” PMD could define a movement disorder that has either clinical or electrophysiologic characteristics that are suggestive of a psychogenic condition but leave room for doubt, such as patients with combined psychogenic and organic movement disorders or with organic movement disorders that have superimposed psychogenic features.

PMDs are mostly generated by conversion or somatoform disorders in which psychological stressors unconsciously produce abnormal movements. They have no known “organic” etiology and may occur in association with underlying psychiatric disease.

The Fahn and Williams classification system, which is the one most commonly used in research and clinical practice, also cannot accurately classify patients who have clinically unequivocal psychogenic features based on distractibility or entrainment but lack false neurologic signs or multiple somatizations that are required for a clinically-established PMD diagnosis; they can only be diagnosed as probable although they meet all the clinical criteria for a “nonorganic” movement disorder, he said.

The classification system insists that probable or possible PMD can be diagnosed with patients who have movement disorders that are consistent and congruent with an organic counterpart, but many of those patients may have an organic movement disorder with a great deal of functional overlay or a combination of organic and nonorganic movement disorders, Dr. Lang said.

“It's very common to see patients with mixed [movements]. They may have some bizarre movement disorder or a phenotype that's difficult to classify but then also have a prominent tremor or dystonia,” he said.

“One of the biggest problems is that we don't have any gold standards in establishing the diagnosis of a psychogenic movement disorder, and the converse is that many organic movement disorders lack similar defining laboratory abnormalities, such as Tourette syndrome or essential tremor.”

Certain clinical phenotypes strongly suggest a PMD, although this is a somewhat controversial area, Dr. Lang said. These include tremors that never vary in amplitude in rest, postural, and action states and certain types of leg tremor, such as prominent thigh tremors. Certain dystonic postures are characteristic of PMDs, such as hemifacial dystonic posture. A lack of arm swing in a patient with hemiparkinsonism may be characteristic of a PMD, because Parkinson's disease patients will bring both arms up in front of them and swing nearly symmetrically despite pronounced bradykinesia.

A revision of the Fahn and Williams scheme might lead to better diagnoses of PMDs. DR. LANG

WASHINGTON – Psychogenic movement disorders could be classified with greater simplicity and possibly diagnosed with greater accuracy in a system that expands the ways in which patients can meet criteria for the disorders, according to Dr. Anthony E. Lang.

The original classification scheme for psychogenic movement disorders (PMDs) proposed by Dr. Stanley Fahn and Dr. Daniel Williams (Adv. Neurol. 1988;50:431-55) subdivided the diagnosis based on the level of diagnostic certainty. The original two categories of “documented” and “clinically established” later merged to become clinically definite PMD (Adv. Neurol. 1995;65:231-57), which are “the majority that we see in the clinics,” said Dr. Lang, professor of neurology at the University of Toronto. Other cases were classified as “probable” or “possible.”

But the Fahn and Williams classification scheme does not take into account the ability to confirm the diagnosis as psychogenic using electrophysiologic testing, Dr. Lang said at an international conference sponsored by the Movement Disorder Society.

Dr. Lang proposed revising the classification scheme to define “clinically definite” PMD as documented, clinically established plus other features (false neurologic signs or psychiatric problems), or clinically established without other features. A “laboratory-supported” definite PMD diagnosis would be made on evidence from electrophysiologic testing. “Possible” PMD could define a movement disorder that has either clinical or electrophysiologic characteristics that are suggestive of a psychogenic condition but leave room for doubt, such as patients with combined psychogenic and organic movement disorders or with organic movement disorders that have superimposed psychogenic features.

PMDs are mostly generated by conversion or somatoform disorders in which psychological stressors unconsciously produce abnormal movements. They have no known “organic” etiology and may occur in association with underlying psychiatric disease.

The Fahn and Williams classification system, which is the one most commonly used in research and clinical practice, also cannot accurately classify patients who have clinically unequivocal psychogenic features based on distractibility or entrainment but lack false neurologic signs or multiple somatizations that are required for a clinically-established PMD diagnosis; they can only be diagnosed as probable although they meet all the clinical criteria for a “nonorganic” movement disorder, he said.

The classification system insists that probable or possible PMD can be diagnosed with patients who have movement disorders that are consistent and congruent with an organic counterpart, but many of those patients may have an organic movement disorder with a great deal of functional overlay or a combination of organic and nonorganic movement disorders, Dr. Lang said.

“It's very common to see patients with mixed [movements]. They may have some bizarre movement disorder or a phenotype that's difficult to classify but then also have a prominent tremor or dystonia,” he said.

“One of the biggest problems is that we don't have any gold standards in establishing the diagnosis of a psychogenic movement disorder, and the converse is that many organic movement disorders lack similar defining laboratory abnormalities, such as Tourette syndrome or essential tremor.”

Certain clinical phenotypes strongly suggest a PMD, although this is a somewhat controversial area, Dr. Lang said. These include tremors that never vary in amplitude in rest, postural, and action states and certain types of leg tremor, such as prominent thigh tremors. Certain dystonic postures are characteristic of PMDs, such as hemifacial dystonic posture. A lack of arm swing in a patient with hemiparkinsonism may be characteristic of a PMD, because Parkinson's disease patients will bring both arms up in front of them and swing nearly symmetrically despite pronounced bradykinesia.

A revision of the Fahn and Williams scheme might lead to better diagnoses of PMDs. DR. LANG

WASHINGTON – Psychogenic movement disorders could be classified with greater simplicity and possibly diagnosed with greater accuracy in a system that expands the ways in which patients can meet criteria for the disorders, according to Dr. Anthony E. Lang.

The original classification scheme for psychogenic movement disorders (PMDs) proposed by Dr. Stanley Fahn and Dr. Daniel Williams (Adv. Neurol. 1988;50:431-55) subdivided the diagnosis based on the level of diagnostic certainty. The original two categories of “documented” and “clinically established” later merged to become clinically definite PMD (Adv. Neurol. 1995;65:231-57), which are “the majority that we see in the clinics,” said Dr. Lang, professor of neurology at the University of Toronto. Other cases were classified as “probable” or “possible.”

But the Fahn and Williams classification scheme does not take into account the ability to confirm the diagnosis as psychogenic using electrophysiologic testing, Dr. Lang said at an international conference sponsored by the Movement Disorder Society.

Dr. Lang proposed revising the classification scheme to define “clinically definite” PMD as documented, clinically established plus other features (false neurologic signs or psychiatric problems), or clinically established without other features. A “laboratory-supported” definite PMD diagnosis would be made on evidence from electrophysiologic testing. “Possible” PMD could define a movement disorder that has either clinical or electrophysiologic characteristics that are suggestive of a psychogenic condition but leave room for doubt, such as patients with combined psychogenic and organic movement disorders or with organic movement disorders that have superimposed psychogenic features.

PMDs are mostly generated by conversion or somatoform disorders in which psychological stressors unconsciously produce abnormal movements. They have no known “organic” etiology and may occur in association with underlying psychiatric disease.

The Fahn and Williams classification system, which is the one most commonly used in research and clinical practice, also cannot accurately classify patients who have clinically unequivocal psychogenic features based on distractibility or entrainment but lack false neurologic signs or multiple somatizations that are required for a clinically-established PMD diagnosis; they can only be diagnosed as probable although they meet all the clinical criteria for a “nonorganic” movement disorder, he said.

The classification system insists that probable or possible PMD can be diagnosed with patients who have movement disorders that are consistent and congruent with an organic counterpart, but many of those patients may have an organic movement disorder with a great deal of functional overlay or a combination of organic and nonorganic movement disorders, Dr. Lang said.

“It's very common to see patients with mixed [movements]. They may have some bizarre movement disorder or a phenotype that's difficult to classify but then also have a prominent tremor or dystonia,” he said.

“One of the biggest problems is that we don't have any gold standards in establishing the diagnosis of a psychogenic movement disorder, and the converse is that many organic movement disorders lack similar defining laboratory abnormalities, such as Tourette syndrome or essential tremor.”

Certain clinical phenotypes strongly suggest a PMD, although this is a somewhat controversial area, Dr. Lang said. These include tremors that never vary in amplitude in rest, postural, and action states and certain types of leg tremor, such as prominent thigh tremors. Certain dystonic postures are characteristic of PMDs, such as hemifacial dystonic posture. A lack of arm swing in a patient with hemiparkinsonism may be characteristic of a PMD, because Parkinson's disease patients will bring both arms up in front of them and swing nearly symmetrically despite pronounced bradykinesia.

A revision of the Fahn and Williams scheme might lead to better diagnoses of PMDs. DR. LANG

WASHINGTON – Neurologists vary widely in their practices and beliefs when it comes to diagnosing and managing patients with psychogenic movement disorders, and those ranges might be indicative of the absence of practice guidelines, according to results from more than 500 Movement Disorder Society members.

The findings revealed a range of approaches in the use of diagnostic testing in making and delivering the diagnosis, and low confidence in the effectiveness of any therapy.

“This is a starting point to determine areas of weaknesses in the diagnostic process and in treatment strategies,” said Dr. Alberto J. Espay, one of the investigators.

Psychogenic movement disorders (PMDs) are mostly generated by conversion or somatoform disorders in which psychological stressors unconsciously produce abnormal movements. They have no known “organic” etiology and may occur in association with underlying psychiatric disease.

Estimates put the number of PMD patients at about 1%-2% of the patient population at general neurology practices, but tertiary movement disorder referral centers have reported as many as 25% of their patients have a PMD, said Dr. Espay, a movement disorders specialist at the University of Cincinnati.

PMDs have been a neglected area of study “because it's so hard to have patients accept the psychological underpinnings of their problem [while] at the same time not stigmatizing them,” said Dr. Espay, who presented the survey results at the Second International Conference on Psychogenic Movement Disorders and Other Conversion Disorders, which was sponsored by the Movement Disorder Society, the National Institute of Neurological Disorders and Stroke, and the National Institute of Mental Health.

He and his colleagues sent the 22-question, online survey to 2,104 members of the Movement Disorder Society and asked that those who did not have experience in managing or diagnosing PMDs not fill it out. Of 519 (25%) neurologists who responded, 43% practice in the United States, 32% in Europe or Canada, and 25% in other countries. Most of them practiced in an academic setting (55%).

In reaching a diagnosis, 74% of the respondents said they ask psychiatrists or other mental health professionals to assess a patient for underlying psychopathology before they discuss the diagnosis with the patient. A majority (52%) said they diagnose and attempt to secure expert management, 40% reported diagnosing and coordinating interdisciplinary long-term management, 5% said they diagnose and personally manage, and 3% diagnose only.

Nearly a quarter said they have no access to an electrophysiology laboratory, but most of those who do use them to confirm PMD only when clinical examination alone is insufficient. Many (40%) said they never or rarely use test results to explain the diagnosis to the patient and 21% said they often or always do so.

The clinical findings of incongruent movement, psychogenic signs, and inconsistency over time were each thought to be essential for a clinically definite diagnosis of PMD by more than half of the respondents and only 8% thought that an obvious psychiatric disturbance was essential for a clinically definite diagnosis.

Fifty-one percent of the respondents said that even when the patient shows clinically definite evidence of PMD, they request a battery of tests such as brain MRI, EEG, and carotid ultrasound, and then present the diagnosis.

In an interview, Dr. Espay called this the “most damning aspect of the survey,” because a PMD diagnosis can be established on clinical evidence alone. Even if such tests produce positive results, they will not explain the problem, because PMDs are not associated with any detectable physiologic or anatomic abnormalities. This approach suggests a many PMD experts “still treat psychogenic movement disorders as a diagnosis of exclusion.”

The respondents indicated that an excessive loss of function or disability relative to what was found in the clinical examination is the greatest predictor of a PMD diagnosis. U.S. respondents were more likely than their overseas counterparts to give a PMD diagnosis if a patient had spontaneous remissions and cures, associated nonphysiologic deficits, a history of mental health problems or psychological stressors, or ongoing litigation related to the patient's condition.

About two-thirds of the respondents reported that they refer PMD patients to a psychiatrist or a mental health specialist while also providing personal follow-up. But about half said mental health professionals at least sometimes question their original diagnosis and recommend that the neurologic basis for the disorder should be reconsidered.

Few respondents rated common treatment strategies such as avoiding iatrogenic harm, patient education, psychotherapy with or without drug therapy, rehabilitation services, and drug therapy for a specific movement impairment as “very” or “extremely” effective.

Slightly more than half of the respondents thought that the identification and management of a concurrent psychiatric disorder or psychological stressor are important predictors of prognosis. Another 60% thought that “acceptance of the diagnosis by the patient” is an extremely important predictor of prognosis.

Dr. Espay said it might be time to survey PMD patients to “determine what happens to them while in psychiatric or psychological care and their odds of following with a treatment strategy.

Dr. Alberto J. Espay says a psychogenic motor disorderdiagnosis can be based on clinical evidence alone. Dan Davenport/AHC Communication Services

WASHINGTON – Neurologists vary widely in their practices and beliefs when it comes to diagnosing and managing patients with psychogenic movement disorders, and those ranges might be indicative of the absence of practice guidelines, according to results from more than 500 Movement Disorder Society members.

The findings revealed a range of approaches in the use of diagnostic testing in making and delivering the diagnosis, and low confidence in the effectiveness of any therapy.

“This is a starting point to determine areas of weaknesses in the diagnostic process and in treatment strategies,” said Dr. Alberto J. Espay, one of the investigators.

Psychogenic movement disorders (PMDs) are mostly generated by conversion or somatoform disorders in which psychological stressors unconsciously produce abnormal movements. They have no known “organic” etiology and may occur in association with underlying psychiatric disease.

Estimates put the number of PMD patients at about 1%-2% of the patient population at general neurology practices, but tertiary movement disorder referral centers have reported as many as 25% of their patients have a PMD, said Dr. Espay, a movement disorders specialist at the University of Cincinnati.

PMDs have been a neglected area of study “because it's so hard to have patients accept the psychological underpinnings of their problem [while] at the same time not stigmatizing them,” said Dr. Espay, who presented the survey results at the Second International Conference on Psychogenic Movement Disorders and Other Conversion Disorders, which was sponsored by the Movement Disorder Society, the National Institute of Neurological Disorders and Stroke, and the National Institute of Mental Health.

He and his colleagues sent the 22-question, online survey to 2,104 members of the Movement Disorder Society and asked that those who did not have experience in managing or diagnosing PMDs not fill it out. Of 519 (25%) neurologists who responded, 43% practice in the United States, 32% in Europe or Canada, and 25% in other countries. Most of them practiced in an academic setting (55%).

In reaching a diagnosis, 74% of the respondents said they ask psychiatrists or other mental health professionals to assess a patient for underlying psychopathology before they discuss the diagnosis with the patient. A majority (52%) said they diagnose and attempt to secure expert management, 40% reported diagnosing and coordinating interdisciplinary long-term management, 5% said they diagnose and personally manage, and 3% diagnose only.

Nearly a quarter said they have no access to an electrophysiology laboratory, but most of those who do use them to confirm PMD only when clinical examination alone is insufficient. Many (40%) said they never or rarely use test results to explain the diagnosis to the patient and 21% said they often or always do so.

The clinical findings of incongruent movement, psychogenic signs, and inconsistency over time were each thought to be essential for a clinically definite diagnosis of PMD by more than half of the respondents and only 8% thought that an obvious psychiatric disturbance was essential for a clinically definite diagnosis.

Fifty-one percent of the respondents said that even when the patient shows clinically definite evidence of PMD, they request a battery of tests such as brain MRI, EEG, and carotid ultrasound, and then present the diagnosis.

In an interview, Dr. Espay called this the “most damning aspect of the survey,” because a PMD diagnosis can be established on clinical evidence alone. Even if such tests produce positive results, they will not explain the problem, because PMDs are not associated with any detectable physiologic or anatomic abnormalities. This approach suggests a many PMD experts “still treat psychogenic movement disorders as a diagnosis of exclusion.”

The respondents indicated that an excessive loss of function or disability relative to what was found in the clinical examination is the greatest predictor of a PMD diagnosis. U.S. respondents were more likely than their overseas counterparts to give a PMD diagnosis if a patient had spontaneous remissions and cures, associated nonphysiologic deficits, a history of mental health problems or psychological stressors, or ongoing litigation related to the patient's condition.

About two-thirds of the respondents reported that they refer PMD patients to a psychiatrist or a mental health specialist while also providing personal follow-up. But about half said mental health professionals at least sometimes question their original diagnosis and recommend that the neurologic basis for the disorder should be reconsidered.

Few respondents rated common treatment strategies such as avoiding iatrogenic harm, patient education, psychotherapy with or without drug therapy, rehabilitation services, and drug therapy for a specific movement impairment as “very” or “extremely” effective.

Slightly more than half of the respondents thought that the identification and management of a concurrent psychiatric disorder or psychological stressor are important predictors of prognosis. Another 60% thought that “acceptance of the diagnosis by the patient” is an extremely important predictor of prognosis.

Dr. Espay said it might be time to survey PMD patients to “determine what happens to them while in psychiatric or psychological care and their odds of following with a treatment strategy.

Dr. Alberto J. Espay says a psychogenic motor disorderdiagnosis can be based on clinical evidence alone. Dan Davenport/AHC Communication Services

WASHINGTON – Neurologists vary widely in their practices and beliefs when it comes to diagnosing and managing patients with psychogenic movement disorders, and those ranges might be indicative of the absence of practice guidelines, according to results from more than 500 Movement Disorder Society members.

The findings revealed a range of approaches in the use of diagnostic testing in making and delivering the diagnosis, and low confidence in the effectiveness of any therapy.

“This is a starting point to determine areas of weaknesses in the diagnostic process and in treatment strategies,” said Dr. Alberto J. Espay, one of the investigators.

Psychogenic movement disorders (PMDs) are mostly generated by conversion or somatoform disorders in which psychological stressors unconsciously produce abnormal movements. They have no known “organic” etiology and may occur in association with underlying psychiatric disease.

Estimates put the number of PMD patients at about 1%-2% of the patient population at general neurology practices, but tertiary movement disorder referral centers have reported as many as 25% of their patients have a PMD, said Dr. Espay, a movement disorders specialist at the University of Cincinnati.

PMDs have been a neglected area of study “because it's so hard to have patients accept the psychological underpinnings of their problem [while] at the same time not stigmatizing them,” said Dr. Espay, who presented the survey results at the Second International Conference on Psychogenic Movement Disorders and Other Conversion Disorders, which was sponsored by the Movement Disorder Society, the National Institute of Neurological Disorders and Stroke, and the National Institute of Mental Health.

He and his colleagues sent the 22-question, online survey to 2,104 members of the Movement Disorder Society and asked that those who did not have experience in managing or diagnosing PMDs not fill it out. Of 519 (25%) neurologists who responded, 43% practice in the United States, 32% in Europe or Canada, and 25% in other countries. Most of them practiced in an academic setting (55%).

In reaching a diagnosis, 74% of the respondents said they ask psychiatrists or other mental health professionals to assess a patient for underlying psychopathology before they discuss the diagnosis with the patient. A majority (52%) said they diagnose and attempt to secure expert management, 40% reported diagnosing and coordinating interdisciplinary long-term management, 5% said they diagnose and personally manage, and 3% diagnose only.

Nearly a quarter said they have no access to an electrophysiology laboratory, but most of those who do use them to confirm PMD only when clinical examination alone is insufficient. Many (40%) said they never or rarely use test results to explain the diagnosis to the patient and 21% said they often or always do so.

The clinical findings of incongruent movement, psychogenic signs, and inconsistency over time were each thought to be essential for a clinically definite diagnosis of PMD by more than half of the respondents and only 8% thought that an obvious psychiatric disturbance was essential for a clinically definite diagnosis.

Fifty-one percent of the respondents said that even when the patient shows clinically definite evidence of PMD, they request a battery of tests such as brain MRI, EEG, and carotid ultrasound, and then present the diagnosis.

In an interview, Dr. Espay called this the “most damning aspect of the survey,” because a PMD diagnosis can be established on clinical evidence alone. Even if such tests produce positive results, they will not explain the problem, because PMDs are not associated with any detectable physiologic or anatomic abnormalities. This approach suggests a many PMD experts “still treat psychogenic movement disorders as a diagnosis of exclusion.”

The respondents indicated that an excessive loss of function or disability relative to what was found in the clinical examination is the greatest predictor of a PMD diagnosis. U.S. respondents were more likely than their overseas counterparts to give a PMD diagnosis if a patient had spontaneous remissions and cures, associated nonphysiologic deficits, a history of mental health problems or psychological stressors, or ongoing litigation related to the patient's condition.

About two-thirds of the respondents reported that they refer PMD patients to a psychiatrist or a mental health specialist while also providing personal follow-up. But about half said mental health professionals at least sometimes question their original diagnosis and recommend that the neurologic basis for the disorder should be reconsidered.

Few respondents rated common treatment strategies such as avoiding iatrogenic harm, patient education, psychotherapy with or without drug therapy, rehabilitation services, and drug therapy for a specific movement impairment as “very” or “extremely” effective.

Slightly more than half of the respondents thought that the identification and management of a concurrent psychiatric disorder or psychological stressor are important predictors of prognosis. Another 60% thought that “acceptance of the diagnosis by the patient” is an extremely important predictor of prognosis.

Dr. Espay said it might be time to survey PMD patients to “determine what happens to them while in psychiatric or psychological care and their odds of following with a treatment strategy.

Dr. Alberto J. Espay says a psychogenic motor disorderdiagnosis can be based on clinical evidence alone. Dan Davenport/AHC Communication Services

Vitamin D appears to interact directly with a key susceptibility locus for multiple sclerosis, serving as an environmental influence that may decrease the risk of the disease in individuals with certain haplotypes, according to a study reported online in PLoS Genetics.

The findings provide “more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS [multiple sclerosis] risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention,” Sreeram V. Ramagopalan, D.Phil., of the University of Oxford (England) and associates reported (PLoS Genetics 2009 Feb. 6 [doi:10.1371/journal.pgen.1000369]).

The prevalence of MS has been shown to decrease across a north-to-south gradient in the northern hemisphere and increase across a north-to-south gradient in the southern hemisphere. Other studies found that patients with MS are deficient in vitamin D, and dietary intake of the vitamin reduces MS risk. Data also suggest that MS risk in the northern latitudes of the northern hemisphere may vary with the season of birth.

However, the association between MS risk and the chromosomal region that the researchers focused on is “weak at best,” even though it is the region known to be most strongly associated with MS in Northern Europeans, Dr. Mark S. Freedman said in an interview.

“As you go around the world… there may well be other HLA susceptibility genes, but we just haven't been able to identify the exact ones,” said Dr. Freedman, director of the multiple sclerosis research unit at Ottawa (Ont.) Hospital and professor of neurology at the University of Ottawa. He was not involved in the study.

Dr. Freedman also noted that the association between vitamin D and MS does not explain why dark-skinned people can develop MS.

In a cell line that carried HLA-DRB1*15, Dr. Ramagopalan and colleagues discovered a functional vitamin D response element (VDRE) near the transcription start of the gene HLA-DRB1, which is located in the large genomic region containing major histocompatibility complex (MHC) class II genes.

The sequence of the VDRE was the same in 322 individuals with or without MS who were homozygous for the HLA-DRB1*15 risk allele. However, nucleotide changes in the VDRE sequences were detected in 168 individuals who were homozygous for other HLA-DRB1 alleles. In a cell line that carried the HLA-DRB1*15 haplotype, the putative VDRE was able to bind to vitamin D receptor, which is known to influence “the rate of transcription of vitamin D responsive genes by acting as a ligand activated transcription factor,” according to the investigators.

Dr. Ramagopalan and coinvestigators then showed that the addition of 1,25-dihydroxyvitmin D3, or calcitriol, to HLA-DRB1 gene constructs with this VDRE significantly increased expression of the HLA-DRB1 gene by 60%. Treatment with 1,25-dihydroxyvitamin D3 also significantly increased the expression of HLA-DRB1 by 30% on the surface of cells that were homozygous for the HLA-DRB1*15 haplotype.

“Given the results of this study, variable expression of HLA-DRB1 could affect central deletion of autoreactive T cells. It is plausible that a lack of vitamin D in utero or early childhood can affect the expression of HLA-DRB1 in the thymus, impacting on central deletion. For MS in HLA-DRB1*15 bearing individuals, a lack of vitamin D during early life could allow autoreactive T cells to escape thymic deletion and thus increase autoimmune disease risk.”

“The intriguing possibility that vitamin D responsiveness rather than any antigen specificity determines the increased MS risk of the HLA-DRB1*15 haplotype warrants consideration and can be tested in the infrequent haplotypes bearing the VDRE on other non-HLA-DRB1*15 haplotypes,” the researchers concluded.

The study was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom.

Vitamin D appears to interact directly with a key susceptibility locus for multiple sclerosis, serving as an environmental influence that may decrease the risk of the disease in individuals with certain haplotypes, according to a study reported online in PLoS Genetics.

The findings provide “more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS [multiple sclerosis] risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention,” Sreeram V. Ramagopalan, D.Phil., of the University of Oxford (England) and associates reported (PLoS Genetics 2009 Feb. 6 [doi:10.1371/journal.pgen.1000369]).

The prevalence of MS has been shown to decrease across a north-to-south gradient in the northern hemisphere and increase across a north-to-south gradient in the southern hemisphere. Other studies found that patients with MS are deficient in vitamin D, and dietary intake of the vitamin reduces MS risk. Data also suggest that MS risk in the northern latitudes of the northern hemisphere may vary with the season of birth.

However, the association between MS risk and the chromosomal region that the researchers focused on is “weak at best,” even though it is the region known to be most strongly associated with MS in Northern Europeans, Dr. Mark S. Freedman said in an interview.

“As you go around the world… there may well be other HLA susceptibility genes, but we just haven't been able to identify the exact ones,” said Dr. Freedman, director of the multiple sclerosis research unit at Ottawa (Ont.) Hospital and professor of neurology at the University of Ottawa. He was not involved in the study.

Dr. Freedman also noted that the association between vitamin D and MS does not explain why dark-skinned people can develop MS.

In a cell line that carried HLA-DRB1*15, Dr. Ramagopalan and colleagues discovered a functional vitamin D response element (VDRE) near the transcription start of the gene HLA-DRB1, which is located in the large genomic region containing major histocompatibility complex (MHC) class II genes.

The sequence of the VDRE was the same in 322 individuals with or without MS who were homozygous for the HLA-DRB1*15 risk allele. However, nucleotide changes in the VDRE sequences were detected in 168 individuals who were homozygous for other HLA-DRB1 alleles. In a cell line that carried the HLA-DRB1*15 haplotype, the putative VDRE was able to bind to vitamin D receptor, which is known to influence “the rate of transcription of vitamin D responsive genes by acting as a ligand activated transcription factor,” according to the investigators.

Dr. Ramagopalan and coinvestigators then showed that the addition of 1,25-dihydroxyvitmin D3, or calcitriol, to HLA-DRB1 gene constructs with this VDRE significantly increased expression of the HLA-DRB1 gene by 60%. Treatment with 1,25-dihydroxyvitamin D3 also significantly increased the expression of HLA-DRB1 by 30% on the surface of cells that were homozygous for the HLA-DRB1*15 haplotype.

“Given the results of this study, variable expression of HLA-DRB1 could affect central deletion of autoreactive T cells. It is plausible that a lack of vitamin D in utero or early childhood can affect the expression of HLA-DRB1 in the thymus, impacting on central deletion. For MS in HLA-DRB1*15 bearing individuals, a lack of vitamin D during early life could allow autoreactive T cells to escape thymic deletion and thus increase autoimmune disease risk.”

“The intriguing possibility that vitamin D responsiveness rather than any antigen specificity determines the increased MS risk of the HLA-DRB1*15 haplotype warrants consideration and can be tested in the infrequent haplotypes bearing the VDRE on other non-HLA-DRB1*15 haplotypes,” the researchers concluded.

The study was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom.

Vitamin D appears to interact directly with a key susceptibility locus for multiple sclerosis, serving as an environmental influence that may decrease the risk of the disease in individuals with certain haplotypes, according to a study reported online in PLoS Genetics.

The findings provide “more direct support for the already strong epidemiological evidence implicating sunlight and vitamin D in the determination of MS [multiple sclerosis] risk, and implies that vitamin D supplementation at critical time periods may be key to disease prevention,” Sreeram V. Ramagopalan, D.Phil., of the University of Oxford (England) and associates reported (PLoS Genetics 2009 Feb. 6 [doi:10.1371/journal.pgen.1000369]).

The prevalence of MS has been shown to decrease across a north-to-south gradient in the northern hemisphere and increase across a north-to-south gradient in the southern hemisphere. Other studies found that patients with MS are deficient in vitamin D, and dietary intake of the vitamin reduces MS risk. Data also suggest that MS risk in the northern latitudes of the northern hemisphere may vary with the season of birth.

However, the association between MS risk and the chromosomal region that the researchers focused on is “weak at best,” even though it is the region known to be most strongly associated with MS in Northern Europeans, Dr. Mark S. Freedman said in an interview.

“As you go around the world… there may well be other HLA susceptibility genes, but we just haven't been able to identify the exact ones,” said Dr. Freedman, director of the multiple sclerosis research unit at Ottawa (Ont.) Hospital and professor of neurology at the University of Ottawa. He was not involved in the study.

Dr. Freedman also noted that the association between vitamin D and MS does not explain why dark-skinned people can develop MS.

In a cell line that carried HLA-DRB1*15, Dr. Ramagopalan and colleagues discovered a functional vitamin D response element (VDRE) near the transcription start of the gene HLA-DRB1, which is located in the large genomic region containing major histocompatibility complex (MHC) class II genes.

The sequence of the VDRE was the same in 322 individuals with or without MS who were homozygous for the HLA-DRB1*15 risk allele. However, nucleotide changes in the VDRE sequences were detected in 168 individuals who were homozygous for other HLA-DRB1 alleles. In a cell line that carried the HLA-DRB1*15 haplotype, the putative VDRE was able to bind to vitamin D receptor, which is known to influence “the rate of transcription of vitamin D responsive genes by acting as a ligand activated transcription factor,” according to the investigators.

Dr. Ramagopalan and coinvestigators then showed that the addition of 1,25-dihydroxyvitmin D3, or calcitriol, to HLA-DRB1 gene constructs with this VDRE significantly increased expression of the HLA-DRB1 gene by 60%. Treatment with 1,25-dihydroxyvitamin D3 also significantly increased the expression of HLA-DRB1 by 30% on the surface of cells that were homozygous for the HLA-DRB1*15 haplotype.

“Given the results of this study, variable expression of HLA-DRB1 could affect central deletion of autoreactive T cells. It is plausible that a lack of vitamin D in utero or early childhood can affect the expression of HLA-DRB1 in the thymus, impacting on central deletion. For MS in HLA-DRB1*15 bearing individuals, a lack of vitamin D during early life could allow autoreactive T cells to escape thymic deletion and thus increase autoimmune disease risk.”

“The intriguing possibility that vitamin D responsiveness rather than any antigen specificity determines the increased MS risk of the HLA-DRB1*15 haplotype warrants consideration and can be tested in the infrequent haplotypes bearing the VDRE on other non-HLA-DRB1*15 haplotypes,” the researchers concluded.

The study was funded by the Multiple Sclerosis Society of Canada Scientific Research Foundation and the Multiple Sclerosis Society of the United Kingdom.

Vaccination with live, attenuated varicella zoster virus was not associated with an increased risk of ischemic stroke in pediatric patients in the year after they received their vaccination, according to a retrospective, population-based study of children registered in the Vaccine Safety DataLink.

The study is the first to systematically examine the association between varicella zoster virus (VZV) vaccination and ischemic stroke. In previous studies, infection with the wild-type VZV has been associated with ischemic stroke in adults following herpes zoster ophthalmicus and in children following primary infection with the virus (chickenpox).

Suspicion of an association between varicella vaccination and ischemic stroke initially arose because of case reports of children with signs and symptoms of ischemic strokes who had been vaccinated with live, attenuated VZV.

In the study of approximately 3.25 million children who were members of eight medical care organizations that participate in the Centers for Disease Control and Prevention's Vaccine Safety DataLink project, strokes were diagnosed in a significantly lower percentage of children who received at least one varicella vaccination than in those who did not receive the vaccine (0.003% vs. 0.008%), James G. Donahue, D.V.M, Ph.D., of the Marshfield (Wisc.) Clinic Research Foundation and his colleagues reported (Pediatrics 2009;123:e228–34).

Although unvaccinated children in the cohort had a significantly older mean age than did vaccinated children (7.9 years vs. 1.9 years) because the vaccine was not widely distributed until the late 1990s, adjustment for age did not alter the results of the analysis.

Dr. David Kimberlin, a member of the American Academy of Pediatrics Committee on Infectious Diseases who specializes in varicella, called the study "definitive."

The study "really shows the power of the Vaccine Safety DataLink. It is a phenomenal means by which complications of vaccinations can be assessed, and in this case, ruled out," Dr. Kimberlin, of the division of pediatric infectious diseases at the University of Alabama, Birmingham, said. He was not involved in the study.

The study included children older than 11 months but younger than 18 years, excluding those diagnosed with infantile cerebral palsy or those who were diagnosed before 11 months of age with stroke, hemiplegia, or hemiparesis. The investigators noted that they analyzed the 12-month period after vaccination because "reports have suggested that the incidence of stroke rarely exceeds 1 year after VZV infection."

Within the study period of 1991–2004, the investigators identified 39 children with an inpatient diagnosis of ischemic stroke out of roughly 1.14 million children in the cohort who had received at least one varicella vaccination, compared with 164 diagnoses of stroke in unvaccinated children. There was no evidence of temporal clustering of the 39 patients who had strokes after vaccination. The risk of stroke was not significantly elevated at any point in time during the 12-month period after vaccination.

Of the 203 children who suffered a stroke, 87 had risk factors for the event.

The study was funded entirely by the Centers for Disease Control and Prevention. Three of the investigators reported that they served as a consultant to or received research support from Merck Pharmaceuticals. One of these investigators also has received research support from Novartis, GlaxoSmithKline, Sanofi Pasteur, and MedImmune.

Vaccination with live, attenuated varicella zoster virus was not associated with an increased risk of ischemic stroke in pediatric patients in the year after they received their vaccination, according to a retrospective, population-based study of children registered in the Vaccine Safety DataLink.

The study is the first to systematically examine the association between varicella zoster virus (VZV) vaccination and ischemic stroke. In previous studies, infection with the wild-type VZV has been associated with ischemic stroke in adults following herpes zoster ophthalmicus and in children following primary infection with the virus (chickenpox).

Suspicion of an association between varicella vaccination and ischemic stroke initially arose because of case reports of children with signs and symptoms of ischemic strokes who had been vaccinated with live, attenuated VZV.

In the study of approximately 3.25 million children who were members of eight medical care organizations that participate in the Centers for Disease Control and Prevention's Vaccine Safety DataLink project, strokes were diagnosed in a significantly lower percentage of children who received at least one varicella vaccination than in those who did not receive the vaccine (0.003% vs. 0.008%), James G. Donahue, D.V.M, Ph.D., of the Marshfield (Wisc.) Clinic Research Foundation and his colleagues reported (Pediatrics 2009;123:e228–34).

Although unvaccinated children in the cohort had a significantly older mean age than did vaccinated children (7.9 years vs. 1.9 years) because the vaccine was not widely distributed until the late 1990s, adjustment for age did not alter the results of the analysis.

Dr. David Kimberlin, a member of the American Academy of Pediatrics Committee on Infectious Diseases who specializes in varicella, called the study "definitive."

The study "really shows the power of the Vaccine Safety DataLink. It is a phenomenal means by which complications of vaccinations can be assessed, and in this case, ruled out," Dr. Kimberlin, of the division of pediatric infectious diseases at the University of Alabama, Birmingham, said. He was not involved in the study.

The study included children older than 11 months but younger than 18 years, excluding those diagnosed with infantile cerebral palsy or those who were diagnosed before 11 months of age with stroke, hemiplegia, or hemiparesis. The investigators noted that they analyzed the 12-month period after vaccination because "reports have suggested that the incidence of stroke rarely exceeds 1 year after VZV infection."

Within the study period of 1991–2004, the investigators identified 39 children with an inpatient diagnosis of ischemic stroke out of roughly 1.14 million children in the cohort who had received at least one varicella vaccination, compared with 164 diagnoses of stroke in unvaccinated children. There was no evidence of temporal clustering of the 39 patients who had strokes after vaccination. The risk of stroke was not significantly elevated at any point in time during the 12-month period after vaccination.

Of the 203 children who suffered a stroke, 87 had risk factors for the event.

The study was funded entirely by the Centers for Disease Control and Prevention. Three of the investigators reported that they served as a consultant to or received research support from Merck Pharmaceuticals. One of these investigators also has received research support from Novartis, GlaxoSmithKline, Sanofi Pasteur, and MedImmune.

Vaccination with live, attenuated varicella zoster virus was not associated with an increased risk of ischemic stroke in pediatric patients in the year after they received their vaccination, according to a retrospective, population-based study of children registered in the Vaccine Safety DataLink.

The study is the first to systematically examine the association between varicella zoster virus (VZV) vaccination and ischemic stroke. In previous studies, infection with the wild-type VZV has been associated with ischemic stroke in adults following herpes zoster ophthalmicus and in children following primary infection with the virus (chickenpox).

Suspicion of an association between varicella vaccination and ischemic stroke initially arose because of case reports of children with signs and symptoms of ischemic strokes who had been vaccinated with live, attenuated VZV.

In the study of approximately 3.25 million children who were members of eight medical care organizations that participate in the Centers for Disease Control and Prevention's Vaccine Safety DataLink project, strokes were diagnosed in a significantly lower percentage of children who received at least one varicella vaccination than in those who did not receive the vaccine (0.003% vs. 0.008%), James G. Donahue, D.V.M, Ph.D., of the Marshfield (Wisc.) Clinic Research Foundation and his colleagues reported (Pediatrics 2009;123:e228–34).

Although unvaccinated children in the cohort had a significantly older mean age than did vaccinated children (7.9 years vs. 1.9 years) because the vaccine was not widely distributed until the late 1990s, adjustment for age did not alter the results of the analysis.

Dr. David Kimberlin, a member of the American Academy of Pediatrics Committee on Infectious Diseases who specializes in varicella, called the study "definitive."

The study "really shows the power of the Vaccine Safety DataLink. It is a phenomenal means by which complications of vaccinations can be assessed, and in this case, ruled out," Dr. Kimberlin, of the division of pediatric infectious diseases at the University of Alabama, Birmingham, said. He was not involved in the study.

The study included children older than 11 months but younger than 18 years, excluding those diagnosed with infantile cerebral palsy or those who were diagnosed before 11 months of age with stroke, hemiplegia, or hemiparesis. The investigators noted that they analyzed the 12-month period after vaccination because "reports have suggested that the incidence of stroke rarely exceeds 1 year after VZV infection."

Within the study period of 1991–2004, the investigators identified 39 children with an inpatient diagnosis of ischemic stroke out of roughly 1.14 million children in the cohort who had received at least one varicella vaccination, compared with 164 diagnoses of stroke in unvaccinated children. There was no evidence of temporal clustering of the 39 patients who had strokes after vaccination. The risk of stroke was not significantly elevated at any point in time during the 12-month period after vaccination.

Of the 203 children who suffered a stroke, 87 had risk factors for the event.

The study was funded entirely by the Centers for Disease Control and Prevention. Three of the investigators reported that they served as a consultant to or received research support from Merck Pharmaceuticals. One of these investigators also has received research support from Novartis, GlaxoSmithKline, Sanofi Pasteur, and MedImmune.

Bariatric surgery procedures in patients with type 2 diabetes have varying effects on the hormones that control insulin secretion and sensitivity, and these effects must be taken into consideration to maintain glycemic control after surgery, according to a review of bariatric surgery studies that reported diabetes-related outcomes.

“Caloric intake is minimal after any bariatric procedure, and patients are at high risk for hypoglycemia if their preoperative regimens are not appropriately adjusted,” Dr. Marion L. Vetter and her associates at the University of Pennsylvania, Philadelphia, wrote.

Bariatric procedures that have been broadly classified as malabsorptive, such as biliopancreatic diversion (BPD), with duodenal switch have been reported to have greater effect on the gastrointestinal hormones known as incretins (which stimulate insulin release after enteral nutrition) than do so-called restrictive procedures, such as laparoscopic adjustable gastric banding (LAGB) and vertical banded gastroplasty (VBG).

Roux-en-Y gastric bypass (RYGB) incorporates both malabsorptive and restrictive properties. In one large meta-analysis of bariatric studies, type 2 diabetes resolved in 84% of patients after RYGB, whereas it resolved in 98% of patients after BPD and in 48%-72% of patients after LAGB or VBG (Ann. Intern. Med. 2009;150:94-103).

Dr. Vetter and her colleagues found that decreased caloric intake has an immediate impact on insulin sensitivity but does not alone account for lower blood glucose levels because studies have shown that complete diabetes resolution occurs within days of intestinal bypass procedures but takes months to occur after LAGB. Even with the same postoperative caloric intake, blood glucose levels have been shown to drop further and faster after RYGB than after VBG.

Changes in the levels of the incretins called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), as well as the levels of non-incretin gut peptides known as peptide YY (PYY) and ghrelin, appear to occur rapidly after gastric bypass. GLP-1 is known to slow gastric emptying. It acts on pancreatic ? islet cells to augment glucose-dependent insulin secretion and on the central nervous system to induce satiety and decrease food intake. GLP-1 remains elevated for 1 year after gastric bypass.

GIP is secreted by cells in the proximal gut and also acts on beta islet cells to increase insulin secretion, but it is less potent than GLP-1 and does not affect gastric emptying or satiety. Lower levels of GIP have been reported, albeit inconsistently, several months after RYGB. Studies of restrictive procedures have not found altered GIP levels.

Specialized cells in the distal ileum produce PYY, which increases satiety and delays gastric emptying. PYY is known to increase as early as 2 days after RYGB and remain elevated for at least 6 weeks, which “may account for the immediate decrease in appetite after surgery,” the researchers wrote. The response of PYY is blunted after meals in patients who underwent gastric banding, but no data exist about its level in the weeks after banding or other restrictive procedures.

Because insulin requirements often rapidly decline after bariatric surgery, the authors suggested that “patients may require only long-acting basal insulin in the immediate postoperative period, with rapid-acting insulin for correction of hyperglycemia as necessary.” They recommended avoiding sulfonylureas and meglitinides until patients begin eating regularly. Thiazolidinediones are safe once regular eating is occurring.

The senior author of the review, Dr. Nayyar Iqbal, is employed by Bristol-Myers Squibb. No other authors reported potential financial conflicts of interest.

Bariatric surgery procedures in patients with type 2 diabetes have varying effects on the hormones that control insulin secretion and sensitivity, and these effects must be taken into consideration to maintain glycemic control after surgery, according to a review of bariatric surgery studies that reported diabetes-related outcomes.

“Caloric intake is minimal after any bariatric procedure, and patients are at high risk for hypoglycemia if their preoperative regimens are not appropriately adjusted,” Dr. Marion L. Vetter and her associates at the University of Pennsylvania, Philadelphia, wrote.

Bariatric procedures that have been broadly classified as malabsorptive, such as biliopancreatic diversion (BPD), with duodenal switch have been reported to have greater effect on the gastrointestinal hormones known as incretins (which stimulate insulin release after enteral nutrition) than do so-called restrictive procedures, such as laparoscopic adjustable gastric banding (LAGB) and vertical banded gastroplasty (VBG).

Roux-en-Y gastric bypass (RYGB) incorporates both malabsorptive and restrictive properties. In one large meta-analysis of bariatric studies, type 2 diabetes resolved in 84% of patients after RYGB, whereas it resolved in 98% of patients after BPD and in 48%-72% of patients after LAGB or VBG (Ann. Intern. Med. 2009;150:94-103).

Dr. Vetter and her colleagues found that decreased caloric intake has an immediate impact on insulin sensitivity but does not alone account for lower blood glucose levels because studies have shown that complete diabetes resolution occurs within days of intestinal bypass procedures but takes months to occur after LAGB. Even with the same postoperative caloric intake, blood glucose levels have been shown to drop further and faster after RYGB than after VBG.

Changes in the levels of the incretins called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), as well as the levels of non-incretin gut peptides known as peptide YY (PYY) and ghrelin, appear to occur rapidly after gastric bypass. GLP-1 is known to slow gastric emptying. It acts on pancreatic ? islet cells to augment glucose-dependent insulin secretion and on the central nervous system to induce satiety and decrease food intake. GLP-1 remains elevated for 1 year after gastric bypass.

GIP is secreted by cells in the proximal gut and also acts on beta islet cells to increase insulin secretion, but it is less potent than GLP-1 and does not affect gastric emptying or satiety. Lower levels of GIP have been reported, albeit inconsistently, several months after RYGB. Studies of restrictive procedures have not found altered GIP levels.

Specialized cells in the distal ileum produce PYY, which increases satiety and delays gastric emptying. PYY is known to increase as early as 2 days after RYGB and remain elevated for at least 6 weeks, which “may account for the immediate decrease in appetite after surgery,” the researchers wrote. The response of PYY is blunted after meals in patients who underwent gastric banding, but no data exist about its level in the weeks after banding or other restrictive procedures.

Because insulin requirements often rapidly decline after bariatric surgery, the authors suggested that “patients may require only long-acting basal insulin in the immediate postoperative period, with rapid-acting insulin for correction of hyperglycemia as necessary.” They recommended avoiding sulfonylureas and meglitinides until patients begin eating regularly. Thiazolidinediones are safe once regular eating is occurring.

The senior author of the review, Dr. Nayyar Iqbal, is employed by Bristol-Myers Squibb. No other authors reported potential financial conflicts of interest.

Bariatric surgery procedures in patients with type 2 diabetes have varying effects on the hormones that control insulin secretion and sensitivity, and these effects must be taken into consideration to maintain glycemic control after surgery, according to a review of bariatric surgery studies that reported diabetes-related outcomes.

“Caloric intake is minimal after any bariatric procedure, and patients are at high risk for hypoglycemia if their preoperative regimens are not appropriately adjusted,” Dr. Marion L. Vetter and her associates at the University of Pennsylvania, Philadelphia, wrote.

Bariatric procedures that have been broadly classified as malabsorptive, such as biliopancreatic diversion (BPD), with duodenal switch have been reported to have greater effect on the gastrointestinal hormones known as incretins (which stimulate insulin release after enteral nutrition) than do so-called restrictive procedures, such as laparoscopic adjustable gastric banding (LAGB) and vertical banded gastroplasty (VBG).

Roux-en-Y gastric bypass (RYGB) incorporates both malabsorptive and restrictive properties. In one large meta-analysis of bariatric studies, type 2 diabetes resolved in 84% of patients after RYGB, whereas it resolved in 98% of patients after BPD and in 48%-72% of patients after LAGB or VBG (Ann. Intern. Med. 2009;150:94-103).

Dr. Vetter and her colleagues found that decreased caloric intake has an immediate impact on insulin sensitivity but does not alone account for lower blood glucose levels because studies have shown that complete diabetes resolution occurs within days of intestinal bypass procedures but takes months to occur after LAGB. Even with the same postoperative caloric intake, blood glucose levels have been shown to drop further and faster after RYGB than after VBG.

Changes in the levels of the incretins called glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), as well as the levels of non-incretin gut peptides known as peptide YY (PYY) and ghrelin, appear to occur rapidly after gastric bypass. GLP-1 is known to slow gastric emptying. It acts on pancreatic ? islet cells to augment glucose-dependent insulin secretion and on the central nervous system to induce satiety and decrease food intake. GLP-1 remains elevated for 1 year after gastric bypass.

GIP is secreted by cells in the proximal gut and also acts on beta islet cells to increase insulin secretion, but it is less potent than GLP-1 and does not affect gastric emptying or satiety. Lower levels of GIP have been reported, albeit inconsistently, several months after RYGB. Studies of restrictive procedures have not found altered GIP levels.

Specialized cells in the distal ileum produce PYY, which increases satiety and delays gastric emptying. PYY is known to increase as early as 2 days after RYGB and remain elevated for at least 6 weeks, which “may account for the immediate decrease in appetite after surgery,” the researchers wrote. The response of PYY is blunted after meals in patients who underwent gastric banding, but no data exist about its level in the weeks after banding or other restrictive procedures.

Because insulin requirements often rapidly decline after bariatric surgery, the authors suggested that “patients may require only long-acting basal insulin in the immediate postoperative period, with rapid-acting insulin for correction of hyperglycemia as necessary.” They recommended avoiding sulfonylureas and meglitinides until patients begin eating regularly. Thiazolidinediones are safe once regular eating is occurring.

The senior author of the review, Dr. Nayyar Iqbal, is employed by Bristol-Myers Squibb. No other authors reported potential financial conflicts of interest.

Vaccination with live, attenuated varicella zoster virus was not associated with an increased risk of ischemic stroke in pediatric patients in the year after they received their vaccination, a retrospective, population-based study of children registered in the Vaccine Safety DataLink shows.

The study is the first to systematically examine the association between varicella zoster virus (VZV) vaccination and ischemic stroke. In previous studies, infection with the wild-type VZV has been associated with ischemic stroke in adults after herpes zoster ophthalmicus and in children after primary infection with the virus (chickenpox). Suspicion of an association between varicella vaccination and ischemic stroke initially arose because of case reports of children with signs and symptoms of ischemic strokes who had been vaccinated with live, attenuated VZV.

In the study of about 3.25 million children who were members of eight medical care organizations that participate in the Centers for Disease Control and Prevention's Vaccine Safety DataLink project, strokes were diagnosed in a significantly lower percentage of children who received at least one varicella vaccination than in those who did not receive the vaccine (0.003% vs. 0.008%), James G. Donahue, D.V.M, Ph.D., of the Marshfield (Wisc.) Clinic Research Foundation and his colleagues reported (Pediatrics 2009;123:e228–34).

Although unvaccinated children had a significantly older mean age than did vaccinated children (7.9 years vs. 1.9 years), because the vaccine was not widely distributed until the late 1990s, adjustment for age did not alter the results of the analysis.

Dr. David Kimberlin, a member of the American Academy of Pediatrics Committee on Infectious Diseases who specializes in varicella, called the study “definitive.” The results show that “using the varicella vaccine can save lives and morbidity among survivors who would have gotten chickenpox, anyway.”

The study “really shows the power of the Vaccine Safety DataLink. It is a phenomenal means by which complications of vaccinations can be assessed, and in this case, ruled out,” Dr. Kimberlin of the division of pediatric infectious diseases at the University of Alabama, Birmingham, said in an interview. He was not involved in the study.

The study included children older than 11 months but younger than 18 years, excluding those diagnosed with infantile cerebral palsy or those who were diagnosed before 11 months of age with stroke, hemiplegia, or hemiparesis. The investigators said that they analyzed the 12 months after vaccination because “reports have suggested that the incidence of stroke rarely exceeds 1 year after VZV infection.”

Within the study period of 1991–2004, the investigators identified 39 children with an inpatient diagnosis of ischemic stroke out of roughly 1.14 million children in the cohort who had received at least one varicella vaccination, compared with 164 diagnoses of stroke in unvaccinated children.

There was no evidence of temporal clustering of the 39 patients who had strokes after vaccination. The risk of stroke was not significantly elevated at any point in time during the 12-month period after vaccination.

The study was funded entirely by the Centers for Disease Control and Prevention.

Three of the investigators reported that they served as a consultant to or received research support from Merck Pharmaceuticals. One of these investigators also has received research support from Novartis, GlaxoSmithKline, Sanofi Pasteur, and MedImmune.

Vaccination with live, attenuated varicella zoster virus was not associated with an increased risk of ischemic stroke in pediatric patients in the year after they received their vaccination, a retrospective, population-based study of children registered in the Vaccine Safety DataLink shows.

The study is the first to systematically examine the association between varicella zoster virus (VZV) vaccination and ischemic stroke. In previous studies, infection with the wild-type VZV has been associated with ischemic stroke in adults after herpes zoster ophthalmicus and in children after primary infection with the virus (chickenpox). Suspicion of an association between varicella vaccination and ischemic stroke initially arose because of case reports of children with signs and symptoms of ischemic strokes who had been vaccinated with live, attenuated VZV.

In the study of about 3.25 million children who were members of eight medical care organizations that participate in the Centers for Disease Control and Prevention's Vaccine Safety DataLink project, strokes were diagnosed in a significantly lower percentage of children who received at least one varicella vaccination than in those who did not receive the vaccine (0.003% vs. 0.008%), James G. Donahue, D.V.M, Ph.D., of the Marshfield (Wisc.) Clinic Research Foundation and his colleagues reported (Pediatrics 2009;123:e228–34).

Although unvaccinated children had a significantly older mean age than did vaccinated children (7.9 years vs. 1.9 years), because the vaccine was not widely distributed until the late 1990s, adjustment for age did not alter the results of the analysis.

Dr. David Kimberlin, a member of the American Academy of Pediatrics Committee on Infectious Diseases who specializes in varicella, called the study “definitive.” The results show that “using the varicella vaccine can save lives and morbidity among survivors who would have gotten chickenpox, anyway.”

The study “really shows the power of the Vaccine Safety DataLink. It is a phenomenal means by which complications of vaccinations can be assessed, and in this case, ruled out,” Dr. Kimberlin of the division of pediatric infectious diseases at the University of Alabama, Birmingham, said in an interview. He was not involved in the study.

The study included children older than 11 months but younger than 18 years, excluding those diagnosed with infantile cerebral palsy or those who were diagnosed before 11 months of age with stroke, hemiplegia, or hemiparesis. The investigators said that they analyzed the 12 months after vaccination because “reports have suggested that the incidence of stroke rarely exceeds 1 year after VZV infection.”

Within the study period of 1991–2004, the investigators identified 39 children with an inpatient diagnosis of ischemic stroke out of roughly 1.14 million children in the cohort who had received at least one varicella vaccination, compared with 164 diagnoses of stroke in unvaccinated children.

There was no evidence of temporal clustering of the 39 patients who had strokes after vaccination. The risk of stroke was not significantly elevated at any point in time during the 12-month period after vaccination.

The study was funded entirely by the Centers for Disease Control and Prevention.

Three of the investigators reported that they served as a consultant to or received research support from Merck Pharmaceuticals. One of these investigators also has received research support from Novartis, GlaxoSmithKline, Sanofi Pasteur, and MedImmune.

Vaccination with live, attenuated varicella zoster virus was not associated with an increased risk of ischemic stroke in pediatric patients in the year after they received their vaccination, a retrospective, population-based study of children registered in the Vaccine Safety DataLink shows.

The study is the first to systematically examine the association between varicella zoster virus (VZV) vaccination and ischemic stroke. In previous studies, infection with the wild-type VZV has been associated with ischemic stroke in adults after herpes zoster ophthalmicus and in children after primary infection with the virus (chickenpox). Suspicion of an association between varicella vaccination and ischemic stroke initially arose because of case reports of children with signs and symptoms of ischemic strokes who had been vaccinated with live, attenuated VZV.

In the study of about 3.25 million children who were members of eight medical care organizations that participate in the Centers for Disease Control and Prevention's Vaccine Safety DataLink project, strokes were diagnosed in a significantly lower percentage of children who received at least one varicella vaccination than in those who did not receive the vaccine (0.003% vs. 0.008%), James G. Donahue, D.V.M, Ph.D., of the Marshfield (Wisc.) Clinic Research Foundation and his colleagues reported (Pediatrics 2009;123:e228–34).

Although unvaccinated children had a significantly older mean age than did vaccinated children (7.9 years vs. 1.9 years), because the vaccine was not widely distributed until the late 1990s, adjustment for age did not alter the results of the analysis.

Dr. David Kimberlin, a member of the American Academy of Pediatrics Committee on Infectious Diseases who specializes in varicella, called the study “definitive.” The results show that “using the varicella vaccine can save lives and morbidity among survivors who would have gotten chickenpox, anyway.”

The study “really shows the power of the Vaccine Safety DataLink. It is a phenomenal means by which complications of vaccinations can be assessed, and in this case, ruled out,” Dr. Kimberlin of the division of pediatric infectious diseases at the University of Alabama, Birmingham, said in an interview. He was not involved in the study.

The study included children older than 11 months but younger than 18 years, excluding those diagnosed with infantile cerebral palsy or those who were diagnosed before 11 months of age with stroke, hemiplegia, or hemiparesis. The investigators said that they analyzed the 12 months after vaccination because “reports have suggested that the incidence of stroke rarely exceeds 1 year after VZV infection.”

Within the study period of 1991–2004, the investigators identified 39 children with an inpatient diagnosis of ischemic stroke out of roughly 1.14 million children in the cohort who had received at least one varicella vaccination, compared with 164 diagnoses of stroke in unvaccinated children.

There was no evidence of temporal clustering of the 39 patients who had strokes after vaccination. The risk of stroke was not significantly elevated at any point in time during the 12-month period after vaccination.

The study was funded entirely by the Centers for Disease Control and Prevention.

Three of the investigators reported that they served as a consultant to or received research support from Merck Pharmaceuticals. One of these investigators also has received research support from Novartis, GlaxoSmithKline, Sanofi Pasteur, and MedImmune.