Neurodevelopmental Disorders

 

DURBAN, SOUTH AFRICA – Children exposed to HIV in utero but uninfected at birth have neurodevelopmental test scores at age 24 months that are comparable with those of unexposed children, based on a study conducted in Botswana and presented by Jean Leidner at the 21st International AIDS Conference.

“These results provide reassurance regarding the potential effects of in-utero HIV and antiretroviral exposure,” declared Ms. Leidner, CEO of Goodtables Data Consulting in Norman, Okla., and the Botswana Harvard AIDS Institute Partnership.

Bruce Jancin/Frontline Medical News

She presented findings from the Tshipidi Study, which included 337 HIV-negative children born in Botswana to HIV-infected mothers and 387 unexposed children of uninfected mothers. All of the children were assessed at age 24 months using the Developmental Milestone Checklist and an adapted version of the Bayley Scales of Infant and Toddler Development – Third Edition.

The two groups of children had virtually identical scores on the cognitive, gross motor, fine motor, expressive language, and receptive language domains measured in the Bayley-III. The same was true for scores on the fine motor, locomotor, language, and personal-social elements of the Developmental Milestone Checklist.

The two groups of children differed in other ways; 17% of the uninfected children exposed to HIV in utero and 8% of the controls were low birth weight. The HIV-exposed children are being raised in a more challenging environment: just 49% have electricity in the home, compared with 64% of control families. Moreover, 53% of the HIV-exposed children and 33% of the controls live under conditions of moderate-to-severe food uncertainty.

Only 8% of the HIV-infected mothers breastfed, whereas breastfeeding was universal among the control group.

More than 99% of the HIV-infected mothers took antiretroviral medication antenatally. Roughly two-thirds were on zidovudine (Retrovir) monotherapy, the rest on a three-drug regimen of nevirapine (Viramune) plus lamivudine/zidovudine (Combivir). These are older antiretrovirals. Additional neurodevelopmental studies are warranted in children with in-utero exposure to newer agents, as well as in older children, Ms. Leidner said.

She reported having no financial conflicts regarding this study, which was funded by the National Institute of Mental Health.

bjancin@frontlinemedcom.com

 

DURBAN, SOUTH AFRICA – Children exposed to HIV in utero but uninfected at birth have neurodevelopmental test scores at age 24 months that are comparable with those of unexposed children, based on a study conducted in Botswana and presented by Jean Leidner at the 21st International AIDS Conference.

“These results provide reassurance regarding the potential effects of in-utero HIV and antiretroviral exposure,” declared Ms. Leidner, CEO of Goodtables Data Consulting in Norman, Okla., and the Botswana Harvard AIDS Institute Partnership.

Bruce Jancin/Frontline Medical News

She presented findings from the Tshipidi Study, which included 337 HIV-negative children born in Botswana to HIV-infected mothers and 387 unexposed children of uninfected mothers. All of the children were assessed at age 24 months using the Developmental Milestone Checklist and an adapted version of the Bayley Scales of Infant and Toddler Development – Third Edition.

The two groups of children had virtually identical scores on the cognitive, gross motor, fine motor, expressive language, and receptive language domains measured in the Bayley-III. The same was true for scores on the fine motor, locomotor, language, and personal-social elements of the Developmental Milestone Checklist.

The two groups of children differed in other ways; 17% of the uninfected children exposed to HIV in utero and 8% of the controls were low birth weight. The HIV-exposed children are being raised in a more challenging environment: just 49% have electricity in the home, compared with 64% of control families. Moreover, 53% of the HIV-exposed children and 33% of the controls live under conditions of moderate-to-severe food uncertainty.

Only 8% of the HIV-infected mothers breastfed, whereas breastfeeding was universal among the control group.

More than 99% of the HIV-infected mothers took antiretroviral medication antenatally. Roughly two-thirds were on zidovudine (Retrovir) monotherapy, the rest on a three-drug regimen of nevirapine (Viramune) plus lamivudine/zidovudine (Combivir). These are older antiretrovirals. Additional neurodevelopmental studies are warranted in children with in-utero exposure to newer agents, as well as in older children, Ms. Leidner said.

She reported having no financial conflicts regarding this study, which was funded by the National Institute of Mental Health.

bjancin@frontlinemedcom.com

 

DURBAN, SOUTH AFRICA – Children exposed to HIV in utero but uninfected at birth have neurodevelopmental test scores at age 24 months that are comparable with those of unexposed children, based on a study conducted in Botswana and presented by Jean Leidner at the 21st International AIDS Conference.

“These results provide reassurance regarding the potential effects of in-utero HIV and antiretroviral exposure,” declared Ms. Leidner, CEO of Goodtables Data Consulting in Norman, Okla., and the Botswana Harvard AIDS Institute Partnership.

Bruce Jancin/Frontline Medical News

She presented findings from the Tshipidi Study, which included 337 HIV-negative children born in Botswana to HIV-infected mothers and 387 unexposed children of uninfected mothers. All of the children were assessed at age 24 months using the Developmental Milestone Checklist and an adapted version of the Bayley Scales of Infant and Toddler Development – Third Edition.

The two groups of children had virtually identical scores on the cognitive, gross motor, fine motor, expressive language, and receptive language domains measured in the Bayley-III. The same was true for scores on the fine motor, locomotor, language, and personal-social elements of the Developmental Milestone Checklist.

The two groups of children differed in other ways; 17% of the uninfected children exposed to HIV in utero and 8% of the controls were low birth weight. The HIV-exposed children are being raised in a more challenging environment: just 49% have electricity in the home, compared with 64% of control families. Moreover, 53% of the HIV-exposed children and 33% of the controls live under conditions of moderate-to-severe food uncertainty.

Only 8% of the HIV-infected mothers breastfed, whereas breastfeeding was universal among the control group.

More than 99% of the HIV-infected mothers took antiretroviral medication antenatally. Roughly two-thirds were on zidovudine (Retrovir) monotherapy, the rest on a three-drug regimen of nevirapine (Viramune) plus lamivudine/zidovudine (Combivir). These are older antiretrovirals. Additional neurodevelopmental studies are warranted in children with in-utero exposure to newer agents, as well as in older children, Ms. Leidner said.

She reported having no financial conflicts regarding this study, which was funded by the National Institute of Mental Health.

bjancin@frontlinemedcom.com

 

Researchers have proposed the term “congenital Zika syndrome” to cover the range of severe damage and developmental abnormalities – including microcephaly – caused by Zika virus infection.

In the Oct. 3 online edition of JAMA Neurology, Adriana Suely de Oliveira Melo, MD, PhD, of the Instituto de Pesquisa Professor Amorim Neto in Campina Grande, Brazil, and her coauthors report on 11 babies with congenital Zika virus infection who were followed from gestation to 6 months of age.

©Devonyu/Thinkstock

Nine of the infants had a head circumference two standard deviations below the gestational age in most infants, with severe cerebral atrophy on abdominal and transvaginal ultrasonography. However, two of the infants had a normal or enlarged head circumference with severe ventriculomegaly.

Researchers observed hypoplasia of the cerebellar vermis and cerebellum in nine patients, while MRI and CT imaging also found that all patients showed callosal hypoplasia, reduced cerebral volume, abnormal cortical development, and subcortical calcifications.

Four of the infants showed gyral disorganization, five showed evidence of pachygyria, and two had lissencephaly (JAMA Neurol. 2016 Oct 3. doi: 10.1001/jamaneurol.2016.3720).

“Although there was variable damage resulting from brain lesions associated with [Zika virus] congenital infection, a common pattern of brain atrophy and changes associated with disturbances in neuronal migration were observed,” the authors wrote. “Some patients presented with mild brain atrophy and calcifications, and others presented with more severe malformations, such as the absence of the thalamus and lissencephaly.”

Three of the infants died after delivery, representing a fatality rate of 27.3%. All three were found to have akinesia deformation sequence or arthrogryposis. One of the three pregnancies also involved polyhydramnios, and the infant was delivered at 36 weeks because of severe maternal respiratory distress.

All but one of the pregnant women had reported a skin rash at a median of 9.5 weeks in the pregnancy, suggesting Zika virus infection was acquired early.

Postmortem tissue analysis of two of the infants who died found Zika virus genome in the brain, cerebellum, spinal cord, and lung; a higher viral load in the tissue of one of the infants was associated with more severe brain damage.

Overall, nine patients tested positive for Zika virus using real-time reverse-transcription polymerase chain

reactions during gestation and/or after birth, while two patients only had serologic evidence of infection.

“It was interesting to note that the viral sequences amplified from patients 1 and 7 after birth gained a new substitution, V23I, which is located in the envelope domain I and may be implicated in viral tropism to different tissues.”

The study was supported by Consellho Nacional de Desenvolvimento e Pesquisa, Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, and Prefeitura Municipal de Campina Grande. No conflicts of interest were declared.

 

Researchers have proposed the term “congenital Zika syndrome” to cover the range of severe damage and developmental abnormalities – including microcephaly – caused by Zika virus infection.

In the Oct. 3 online edition of JAMA Neurology, Adriana Suely de Oliveira Melo, MD, PhD, of the Instituto de Pesquisa Professor Amorim Neto in Campina Grande, Brazil, and her coauthors report on 11 babies with congenital Zika virus infection who were followed from gestation to 6 months of age.

©Devonyu/Thinkstock

Nine of the infants had a head circumference two standard deviations below the gestational age in most infants, with severe cerebral atrophy on abdominal and transvaginal ultrasonography. However, two of the infants had a normal or enlarged head circumference with severe ventriculomegaly.

Researchers observed hypoplasia of the cerebellar vermis and cerebellum in nine patients, while MRI and CT imaging also found that all patients showed callosal hypoplasia, reduced cerebral volume, abnormal cortical development, and subcortical calcifications.

Four of the infants showed gyral disorganization, five showed evidence of pachygyria, and two had lissencephaly (JAMA Neurol. 2016 Oct 3. doi: 10.1001/jamaneurol.2016.3720).

“Although there was variable damage resulting from brain lesions associated with [Zika virus] congenital infection, a common pattern of brain atrophy and changes associated with disturbances in neuronal migration were observed,” the authors wrote. “Some patients presented with mild brain atrophy and calcifications, and others presented with more severe malformations, such as the absence of the thalamus and lissencephaly.”

Three of the infants died after delivery, representing a fatality rate of 27.3%. All three were found to have akinesia deformation sequence or arthrogryposis. One of the three pregnancies also involved polyhydramnios, and the infant was delivered at 36 weeks because of severe maternal respiratory distress.

All but one of the pregnant women had reported a skin rash at a median of 9.5 weeks in the pregnancy, suggesting Zika virus infection was acquired early.

Postmortem tissue analysis of two of the infants who died found Zika virus genome in the brain, cerebellum, spinal cord, and lung; a higher viral load in the tissue of one of the infants was associated with more severe brain damage.

Overall, nine patients tested positive for Zika virus using real-time reverse-transcription polymerase chain

reactions during gestation and/or after birth, while two patients only had serologic evidence of infection.

“It was interesting to note that the viral sequences amplified from patients 1 and 7 after birth gained a new substitution, V23I, which is located in the envelope domain I and may be implicated in viral tropism to different tissues.”

The study was supported by Consellho Nacional de Desenvolvimento e Pesquisa, Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, and Prefeitura Municipal de Campina Grande. No conflicts of interest were declared.

 

Researchers have proposed the term “congenital Zika syndrome” to cover the range of severe damage and developmental abnormalities – including microcephaly – caused by Zika virus infection.

In the Oct. 3 online edition of JAMA Neurology, Adriana Suely de Oliveira Melo, MD, PhD, of the Instituto de Pesquisa Professor Amorim Neto in Campina Grande, Brazil, and her coauthors report on 11 babies with congenital Zika virus infection who were followed from gestation to 6 months of age.

©Devonyu/Thinkstock

Nine of the infants had a head circumference two standard deviations below the gestational age in most infants, with severe cerebral atrophy on abdominal and transvaginal ultrasonography. However, two of the infants had a normal or enlarged head circumference with severe ventriculomegaly.

Researchers observed hypoplasia of the cerebellar vermis and cerebellum in nine patients, while MRI and CT imaging also found that all patients showed callosal hypoplasia, reduced cerebral volume, abnormal cortical development, and subcortical calcifications.

Four of the infants showed gyral disorganization, five showed evidence of pachygyria, and two had lissencephaly (JAMA Neurol. 2016 Oct 3. doi: 10.1001/jamaneurol.2016.3720).

“Although there was variable damage resulting from brain lesions associated with [Zika virus] congenital infection, a common pattern of brain atrophy and changes associated with disturbances in neuronal migration were observed,” the authors wrote. “Some patients presented with mild brain atrophy and calcifications, and others presented with more severe malformations, such as the absence of the thalamus and lissencephaly.”

Three of the infants died after delivery, representing a fatality rate of 27.3%. All three were found to have akinesia deformation sequence or arthrogryposis. One of the three pregnancies also involved polyhydramnios, and the infant was delivered at 36 weeks because of severe maternal respiratory distress.

All but one of the pregnant women had reported a skin rash at a median of 9.5 weeks in the pregnancy, suggesting Zika virus infection was acquired early.

Postmortem tissue analysis of two of the infants who died found Zika virus genome in the brain, cerebellum, spinal cord, and lung; a higher viral load in the tissue of one of the infants was associated with more severe brain damage.

Overall, nine patients tested positive for Zika virus using real-time reverse-transcription polymerase chain

reactions during gestation and/or after birth, while two patients only had serologic evidence of infection.

“It was interesting to note that the viral sequences amplified from patients 1 and 7 after birth gained a new substitution, V23I, which is located in the envelope domain I and may be implicated in viral tropism to different tissues.”

The study was supported by Consellho Nacional de Desenvolvimento e Pesquisa, Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, and Prefeitura Municipal de Campina Grande. No conflicts of interest were declared.

An elevated rate of autism traits was seen among a cohort of children exposed to antiepileptic drugs (AEDs) in utero. Study findings were reported in the July Epilepsia. “The most important determinant of association with autistic traits was higher doses of sodium valproate exposure,” said Amanda G. Wood, PhD, MPsych, a Senior Lecturer in the School of Psychology at the University of Birmingham in the United Kingdom.

While the use of valproate in women who may become pregnant is generally avoided, there are insufficient data regarding the risk of autism spectrum disorders with low-dose valproate. “If this risk is no greater than with other AEDs, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child,” Dr. Wood said.

Dr. Wood and colleagues conducted a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. Participants were 105 Australian children ages 6 to 8 who were recruited through the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS).

Among the cohort, 11 children (10.5%) had elevated CARS scores, and this proportion was substantially higher than the estimated prevalence of autism spectrum disorders in age-matched children nationally or internationally. Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal IQ, and socioeconomic status.

Children who had in utero exposure to valproate were most likely to have elevated CARS scores, with 7.7% of the valproate monotherapy group and 46.7% of the valproate polytherapy group displaying autism spectrum disorder symptoms. The dose of valproate taken during pregnancy was found to be an independent risk factor for elevated CARS scores, whereas polytherapy was not. “CARS scores were not elevated in children exposed to polytherapy without valproate, suggesting that valproate, or valproate dose, rather than polytherapy per se, is the critical determinant of the relationship,” the researchers said.

—Glenn S. Williams

An elevated rate of autism traits was seen among a cohort of children exposed to antiepileptic drugs (AEDs) in utero. Study findings were reported in the July Epilepsia. “The most important determinant of association with autistic traits was higher doses of sodium valproate exposure,” said Amanda G. Wood, PhD, MPsych, a Senior Lecturer in the School of Psychology at the University of Birmingham in the United Kingdom.

While the use of valproate in women who may become pregnant is generally avoided, there are insufficient data regarding the risk of autism spectrum disorders with low-dose valproate. “If this risk is no greater than with other AEDs, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child,” Dr. Wood said.

Dr. Wood and colleagues conducted a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. Participants were 105 Australian children ages 6 to 8 who were recruited through the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS).

Among the cohort, 11 children (10.5%) had elevated CARS scores, and this proportion was substantially higher than the estimated prevalence of autism spectrum disorders in age-matched children nationally or internationally. Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal IQ, and socioeconomic status.

Children who had in utero exposure to valproate were most likely to have elevated CARS scores, with 7.7% of the valproate monotherapy group and 46.7% of the valproate polytherapy group displaying autism spectrum disorder symptoms. The dose of valproate taken during pregnancy was found to be an independent risk factor for elevated CARS scores, whereas polytherapy was not. “CARS scores were not elevated in children exposed to polytherapy without valproate, suggesting that valproate, or valproate dose, rather than polytherapy per se, is the critical determinant of the relationship,” the researchers said.

—Glenn S. Williams

An elevated rate of autism traits was seen among a cohort of children exposed to antiepileptic drugs (AEDs) in utero. Study findings were reported in the July Epilepsia. “The most important determinant of association with autistic traits was higher doses of sodium valproate exposure,” said Amanda G. Wood, PhD, MPsych, a Senior Lecturer in the School of Psychology at the University of Birmingham in the United Kingdom.

While the use of valproate in women who may become pregnant is generally avoided, there are insufficient data regarding the risk of autism spectrum disorders with low-dose valproate. “If this risk is no greater than with other AEDs, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child,” Dr. Wood said.

Dr. Wood and colleagues conducted a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. Participants were 105 Australian children ages 6 to 8 who were recruited through the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS).

Among the cohort, 11 children (10.5%) had elevated CARS scores, and this proportion was substantially higher than the estimated prevalence of autism spectrum disorders in age-matched children nationally or internationally. Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal IQ, and socioeconomic status.

Children who had in utero exposure to valproate were most likely to have elevated CARS scores, with 7.7% of the valproate monotherapy group and 46.7% of the valproate polytherapy group displaying autism spectrum disorder symptoms. The dose of valproate taken during pregnancy was found to be an independent risk factor for elevated CARS scores, whereas polytherapy was not. “CARS scores were not elevated in children exposed to polytherapy without valproate, suggesting that valproate, or valproate dose, rather than polytherapy per se, is the critical determinant of the relationship,” the researchers said.

—Glenn S. Williams

COLUMBUS, OHIO—Among children with sickle cell disease, type of disease and presence of comorbidities may increase the risk for attentional or behavioral problems, according to research presented at the 43rd Annual Meeting of the Child Neurology Society. Demographics and disease complications also may influence the risk of neurodevelopmental disorders among these children.

“Earlier identification of pediatric patients with sickle cell disease and attention deficit hyperactivity disorder (ADHD), intellectual disability, and specific learning disabilities will allow faster treatment of these disorders and may improve academic performance and quality of life,” said Eboni I. Lance, MD, Co-Medical Director of the Sickle Cell Neurodevelopmental Clinic at Kennedy Krieger Institute in Baltimore.

ADHD Was Common Among Participants
From May 2012 to March 2014, Dr. Lance and colleagues conducted a retrospective chart review of children with sickle cell disease who presented to Kennedy Krieger Institute or Johns Hopkins Hospital. The investigators reviewed the charts for documentation of neurodevelopmental diagnoses such as ADHD; attentional problems; behavioral problems; executive dysfunction; learning disabilities in math, reading, and reading comprehension; intellectual disabilities; developmental delay; fine motor disorders; language disorders; and autism spectrum disorders. The researchers also extracted from the charts data about age, genotype of sickle cell disease, disease complication history, treatments, and school services.

A total of 59 children met inclusion criteria, including 18 who presented to Kennedy Krieger Institute and 41 who presented to Johns Hopkins Hospital. Patients’ average age was 17, and 58% of participants were male. Nearly all (97%) of the children were African American. About 63% of the children had hemoglobin SS type sickle cell disease, 20% had hemoglobin SC, and 10% had hemoglobin S-Beta thalassemia.

When the researchers reviewed participants’ neurodevelopmental diagnoses, they found that 19% of patients had ADHD, 19% had developmental delay, 12% had attention problems, 12% had learning disabilities in math, and 12% had learning disabilities in reading comprehension. Also, 10% of participants had a language disorder, 8% had anxiety, and 8% had behavioral problems.

Associations and Risks for Neurodevelopmental Disorders
Children with hemoglobin S-Beta thalassemia plus or null had significantly higher odds of attention problems than children with the hemoglobin SS type of sickle cell disease. Children with sickle cell disease and a history of asthma had significantly greater odds of behavioral problems than children with sickle cell disease without a history of asthma, even after adjustment for gender and sickle cell disease type. The investigators found no other significant relationships between other neurodevelopmental disorders and demographic characteristics or disease-related complications. They noted that stroke was not associated with significantly increased risk of a specific neurodevelopmental diagnosis, in comparison with other neurodevelopmental disorders.

“There may be differences in the disease phenotype, demographics, and prevalence of certain neurodevelopmental disorders within the pediatric sickle cell disease population,” said Dr. Lance. “Children with sickle cell disease should be screened for neurodevelopmental disorders, with emphasis on specific disease-related characteristics and complications as potential risk factors,” added Dr. Lance. “Specifically, evaluations should include a detailed sickle cell disease history of disease characteristics and complications, as well the typical history of neurologic complications and neurodevelopmental symptoms.”

—Erik Greb

COLUMBUS, OHIO—Among children with sickle cell disease, type of disease and presence of comorbidities may increase the risk for attentional or behavioral problems, according to research presented at the 43rd Annual Meeting of the Child Neurology Society. Demographics and disease complications also may influence the risk of neurodevelopmental disorders among these children.

“Earlier identification of pediatric patients with sickle cell disease and attention deficit hyperactivity disorder (ADHD), intellectual disability, and specific learning disabilities will allow faster treatment of these disorders and may improve academic performance and quality of life,” said Eboni I. Lance, MD, Co-Medical Director of the Sickle Cell Neurodevelopmental Clinic at Kennedy Krieger Institute in Baltimore.

ADHD Was Common Among Participants
From May 2012 to March 2014, Dr. Lance and colleagues conducted a retrospective chart review of children with sickle cell disease who presented to Kennedy Krieger Institute or Johns Hopkins Hospital. The investigators reviewed the charts for documentation of neurodevelopmental diagnoses such as ADHD; attentional problems; behavioral problems; executive dysfunction; learning disabilities in math, reading, and reading comprehension; intellectual disabilities; developmental delay; fine motor disorders; language disorders; and autism spectrum disorders. The researchers also extracted from the charts data about age, genotype of sickle cell disease, disease complication history, treatments, and school services.

A total of 59 children met inclusion criteria, including 18 who presented to Kennedy Krieger Institute and 41 who presented to Johns Hopkins Hospital. Patients’ average age was 17, and 58% of participants were male. Nearly all (97%) of the children were African American. About 63% of the children had hemoglobin SS type sickle cell disease, 20% had hemoglobin SC, and 10% had hemoglobin S-Beta thalassemia.

When the researchers reviewed participants’ neurodevelopmental diagnoses, they found that 19% of patients had ADHD, 19% had developmental delay, 12% had attention problems, 12% had learning disabilities in math, and 12% had learning disabilities in reading comprehension. Also, 10% of participants had a language disorder, 8% had anxiety, and 8% had behavioral problems.

Associations and Risks for Neurodevelopmental Disorders
Children with hemoglobin S-Beta thalassemia plus or null had significantly higher odds of attention problems than children with the hemoglobin SS type of sickle cell disease. Children with sickle cell disease and a history of asthma had significantly greater odds of behavioral problems than children with sickle cell disease without a history of asthma, even after adjustment for gender and sickle cell disease type. The investigators found no other significant relationships between other neurodevelopmental disorders and demographic characteristics or disease-related complications. They noted that stroke was not associated with significantly increased risk of a specific neurodevelopmental diagnosis, in comparison with other neurodevelopmental disorders.

“There may be differences in the disease phenotype, demographics, and prevalence of certain neurodevelopmental disorders within the pediatric sickle cell disease population,” said Dr. Lance. “Children with sickle cell disease should be screened for neurodevelopmental disorders, with emphasis on specific disease-related characteristics and complications as potential risk factors,” added Dr. Lance. “Specifically, evaluations should include a detailed sickle cell disease history of disease characteristics and complications, as well the typical history of neurologic complications and neurodevelopmental symptoms.”

—Erik Greb

COLUMBUS, OHIO—Among children with sickle cell disease, type of disease and presence of comorbidities may increase the risk for attentional or behavioral problems, according to research presented at the 43rd Annual Meeting of the Child Neurology Society. Demographics and disease complications also may influence the risk of neurodevelopmental disorders among these children.

“Earlier identification of pediatric patients with sickle cell disease and attention deficit hyperactivity disorder (ADHD), intellectual disability, and specific learning disabilities will allow faster treatment of these disorders and may improve academic performance and quality of life,” said Eboni I. Lance, MD, Co-Medical Director of the Sickle Cell Neurodevelopmental Clinic at Kennedy Krieger Institute in Baltimore.

ADHD Was Common Among Participants
From May 2012 to March 2014, Dr. Lance and colleagues conducted a retrospective chart review of children with sickle cell disease who presented to Kennedy Krieger Institute or Johns Hopkins Hospital. The investigators reviewed the charts for documentation of neurodevelopmental diagnoses such as ADHD; attentional problems; behavioral problems; executive dysfunction; learning disabilities in math, reading, and reading comprehension; intellectual disabilities; developmental delay; fine motor disorders; language disorders; and autism spectrum disorders. The researchers also extracted from the charts data about age, genotype of sickle cell disease, disease complication history, treatments, and school services.

A total of 59 children met inclusion criteria, including 18 who presented to Kennedy Krieger Institute and 41 who presented to Johns Hopkins Hospital. Patients’ average age was 17, and 58% of participants were male. Nearly all (97%) of the children were African American. About 63% of the children had hemoglobin SS type sickle cell disease, 20% had hemoglobin SC, and 10% had hemoglobin S-Beta thalassemia.

When the researchers reviewed participants’ neurodevelopmental diagnoses, they found that 19% of patients had ADHD, 19% had developmental delay, 12% had attention problems, 12% had learning disabilities in math, and 12% had learning disabilities in reading comprehension. Also, 10% of participants had a language disorder, 8% had anxiety, and 8% had behavioral problems.

Associations and Risks for Neurodevelopmental Disorders
Children with hemoglobin S-Beta thalassemia plus or null had significantly higher odds of attention problems than children with the hemoglobin SS type of sickle cell disease. Children with sickle cell disease and a history of asthma had significantly greater odds of behavioral problems than children with sickle cell disease without a history of asthma, even after adjustment for gender and sickle cell disease type. The investigators found no other significant relationships between other neurodevelopmental disorders and demographic characteristics or disease-related complications. They noted that stroke was not associated with significantly increased risk of a specific neurodevelopmental diagnosis, in comparison with other neurodevelopmental disorders.

“There may be differences in the disease phenotype, demographics, and prevalence of certain neurodevelopmental disorders within the pediatric sickle cell disease population,” said Dr. Lance. “Children with sickle cell disease should be screened for neurodevelopmental disorders, with emphasis on specific disease-related characteristics and complications as potential risk factors,” added Dr. Lance. “Specifically, evaluations should include a detailed sickle cell disease history of disease characteristics and complications, as well the typical history of neurologic complications and neurodevelopmental symptoms.”

—Erik Greb

Sulforaphane, a chemical derived from broccoli sprouts, may ease classic behavioral symptoms in patients with autism spectrum disorders (ASDs), according to a study published online ahead of print October 13 in the Proceedings of the National Academy of Sciences.

The study involved 40 males, ages 13 to 27, with moderate to severe autism. Many participants who received a daily dose of sulforaphane experienced substantial improvements in their social interaction and verbal communication, along with decreases in repetitive, ritualistic behaviors, compared with those who received a placebo, according to the researchers.

“We believe that this may be preliminary evidence for the first treatment for autism that improves symptoms by apparently correcting some of the underlying cellular problems,” said Paul Talalay, MD, Professor of Pharmacology and Molecular Sciences at Johns Hopkins University in Baltimore.

“We are far from being able to declare a victory over autism, but this gives us important insights into what might help,” said coinvestigator Andrew Zimmerman, MD, Professor of Pediatric Neurology at UMass Memorial Medical Center in Worcester.

Cause of Autism Is Elusive
Researchers estimate that ASD affects 1% to 2% of the world’s population, with a much higher incidence in boys than in girls. Its behavioral symptoms, such as poor social interaction and verbal communication, are well known and were first described 70 years ago by Leo Kanner, MD.

Unfortunately, its root causes remain elusive, though progress has been made, Dr. Talalay said, in describing some of the biochemical and molecular abnormalities that tend to accompany ASD. Many of these are related to the efficiency of energy generation in cells. Studies show that the cells of patients with ASD often have high levels of oxidative stress, the buildup of harmful, unintended byproducts from the cell’s use of oxygen that can cause inflammation, damage DNA, and lead to cancer and other chronic diseases.

In 1992, Dr. Talalay’s research group found that sulforaphane can bolster the body’s natural defenses against oxidative stress, inflammation, and DNA damage. In addition, the chemical later was found to improve the body’s heat-shock response, a cascade of events used to protect cells from the stress caused by high temperatures, including those experienced when people have fever.

About one-half of parents report that their children’s autistic behavior improves noticeably when they have a fever, then reverts back when the fever is gone. In 2007, Dr. Zimmerman tested this anecdotal trend clinically and found it to be true, though a mechanism for the fever effect was not identified. Because fevers, similar to sulforaphane, initiate the body’s heat-shock response, Drs. Zimmerman and Talalay wondered if sulforaphane could cause the same temporary improvement in autism that fevers do.

Improvement Linked to Sulforaphane
Before the start of the trial, the patients’ caregivers and physicians filled out three standard behavioral assessments—the Aberrant Behavior Checklist (ABC), the Social Responsiveness Scale (SRS), and the Clinical Global Impressions-Improvement scale (CGI-I). The assessments measure sensory sensitivities, ability to relate to others, verbal communication skills, social interactions, and other behaviors related to autism. Twenty-six participants were randomly selected to receive, based on their weight, 9 to 27 mg of sulforaphane daily, and 14 received placebo. Behavioral assessments were again completed at four, 10, and 18 weeks while treatment continued. A final assessment was completed for most of the participants four weeks after the treatment had stopped.

Most subjects who responded to sulforaphane showed significant improvements by the first measurement at four weeks and continued to improve during the rest of the treatment. After 18 weeks of treatment, the average ABC and SRS scores of those who received sulforaphane had decreased 34% and 17%, respectively, with improvements in bouts of irritability, lethargy, repetitive movements, hyperactivity, awareness, communication, motivation, and mannerisms.

After 18 weeks of treatment, according to the CGI-I scale, 46%, 54%, and 42% of sulforaphane recipients experienced noticeable improvements in social interaction, aberrant behaviors, and verbal communication, respectively.

Dr. Talalay noted that the scores of those who took sulforaphane trended back toward their original values after they stopped taking the chemical, similar to what happens to those who experience improvements during a fever. “It seems like sulforaphane is temporarily helping cells to cope with their handicaps,” he said.

Dr. Zimmerman added that before his group learned which subjects received the sulforaphane or placebo, the impressions of the clinical team, including parents, were that 13 participants noticeably improved. For example, some treated subjects looked them in the eye and shook their hands, which they had not done before. They found out later that all 13 had been taking sulforaphane, which is half of the treatment group. Dr. Talalay cautioned that the levels of sulforaphane precursors present in different varieties of broccoli are highly variable. Furthermore, the capacity of individuals to convert these precursors to active sulforaphane also varies greatly. It would be difficult, he noted, to achieve the levels of sulforaphane used in this study by eating large amounts of broccoli or other cruciferous vegetables.

Sulforaphane, a chemical derived from broccoli sprouts, may ease classic behavioral symptoms in patients with autism spectrum disorders (ASDs), according to a study published online ahead of print October 13 in the Proceedings of the National Academy of Sciences.

The study involved 40 males, ages 13 to 27, with moderate to severe autism. Many participants who received a daily dose of sulforaphane experienced substantial improvements in their social interaction and verbal communication, along with decreases in repetitive, ritualistic behaviors, compared with those who received a placebo, according to the researchers.

“We believe that this may be preliminary evidence for the first treatment for autism that improves symptoms by apparently correcting some of the underlying cellular problems,” said Paul Talalay, MD, Professor of Pharmacology and Molecular Sciences at Johns Hopkins University in Baltimore.

“We are far from being able to declare a victory over autism, but this gives us important insights into what might help,” said coinvestigator Andrew Zimmerman, MD, Professor of Pediatric Neurology at UMass Memorial Medical Center in Worcester.

Cause of Autism Is Elusive
Researchers estimate that ASD affects 1% to 2% of the world’s population, with a much higher incidence in boys than in girls. Its behavioral symptoms, such as poor social interaction and verbal communication, are well known and were first described 70 years ago by Leo Kanner, MD.

Unfortunately, its root causes remain elusive, though progress has been made, Dr. Talalay said, in describing some of the biochemical and molecular abnormalities that tend to accompany ASD. Many of these are related to the efficiency of energy generation in cells. Studies show that the cells of patients with ASD often have high levels of oxidative stress, the buildup of harmful, unintended byproducts from the cell’s use of oxygen that can cause inflammation, damage DNA, and lead to cancer and other chronic diseases.

In 1992, Dr. Talalay’s research group found that sulforaphane can bolster the body’s natural defenses against oxidative stress, inflammation, and DNA damage. In addition, the chemical later was found to improve the body’s heat-shock response, a cascade of events used to protect cells from the stress caused by high temperatures, including those experienced when people have fever.

About one-half of parents report that their children’s autistic behavior improves noticeably when they have a fever, then reverts back when the fever is gone. In 2007, Dr. Zimmerman tested this anecdotal trend clinically and found it to be true, though a mechanism for the fever effect was not identified. Because fevers, similar to sulforaphane, initiate the body’s heat-shock response, Drs. Zimmerman and Talalay wondered if sulforaphane could cause the same temporary improvement in autism that fevers do.

Improvement Linked to Sulforaphane
Before the start of the trial, the patients’ caregivers and physicians filled out three standard behavioral assessments—the Aberrant Behavior Checklist (ABC), the Social Responsiveness Scale (SRS), and the Clinical Global Impressions-Improvement scale (CGI-I). The assessments measure sensory sensitivities, ability to relate to others, verbal communication skills, social interactions, and other behaviors related to autism. Twenty-six participants were randomly selected to receive, based on their weight, 9 to 27 mg of sulforaphane daily, and 14 received placebo. Behavioral assessments were again completed at four, 10, and 18 weeks while treatment continued. A final assessment was completed for most of the participants four weeks after the treatment had stopped.

Most subjects who responded to sulforaphane showed significant improvements by the first measurement at four weeks and continued to improve during the rest of the treatment. After 18 weeks of treatment, the average ABC and SRS scores of those who received sulforaphane had decreased 34% and 17%, respectively, with improvements in bouts of irritability, lethargy, repetitive movements, hyperactivity, awareness, communication, motivation, and mannerisms.

After 18 weeks of treatment, according to the CGI-I scale, 46%, 54%, and 42% of sulforaphane recipients experienced noticeable improvements in social interaction, aberrant behaviors, and verbal communication, respectively.

Dr. Talalay noted that the scores of those who took sulforaphane trended back toward their original values after they stopped taking the chemical, similar to what happens to those who experience improvements during a fever. “It seems like sulforaphane is temporarily helping cells to cope with their handicaps,” he said.

Dr. Zimmerman added that before his group learned which subjects received the sulforaphane or placebo, the impressions of the clinical team, including parents, were that 13 participants noticeably improved. For example, some treated subjects looked them in the eye and shook their hands, which they had not done before. They found out later that all 13 had been taking sulforaphane, which is half of the treatment group. Dr. Talalay cautioned that the levels of sulforaphane precursors present in different varieties of broccoli are highly variable. Furthermore, the capacity of individuals to convert these precursors to active sulforaphane also varies greatly. It would be difficult, he noted, to achieve the levels of sulforaphane used in this study by eating large amounts of broccoli or other cruciferous vegetables.

Sulforaphane, a chemical derived from broccoli sprouts, may ease classic behavioral symptoms in patients with autism spectrum disorders (ASDs), according to a study published online ahead of print October 13 in the Proceedings of the National Academy of Sciences.

The study involved 40 males, ages 13 to 27, with moderate to severe autism. Many participants who received a daily dose of sulforaphane experienced substantial improvements in their social interaction and verbal communication, along with decreases in repetitive, ritualistic behaviors, compared with those who received a placebo, according to the researchers.

“We believe that this may be preliminary evidence for the first treatment for autism that improves symptoms by apparently correcting some of the underlying cellular problems,” said Paul Talalay, MD, Professor of Pharmacology and Molecular Sciences at Johns Hopkins University in Baltimore.

“We are far from being able to declare a victory over autism, but this gives us important insights into what might help,” said coinvestigator Andrew Zimmerman, MD, Professor of Pediatric Neurology at UMass Memorial Medical Center in Worcester.

Cause of Autism Is Elusive
Researchers estimate that ASD affects 1% to 2% of the world’s population, with a much higher incidence in boys than in girls. Its behavioral symptoms, such as poor social interaction and verbal communication, are well known and were first described 70 years ago by Leo Kanner, MD.

Unfortunately, its root causes remain elusive, though progress has been made, Dr. Talalay said, in describing some of the biochemical and molecular abnormalities that tend to accompany ASD. Many of these are related to the efficiency of energy generation in cells. Studies show that the cells of patients with ASD often have high levels of oxidative stress, the buildup of harmful, unintended byproducts from the cell’s use of oxygen that can cause inflammation, damage DNA, and lead to cancer and other chronic diseases.

In 1992, Dr. Talalay’s research group found that sulforaphane can bolster the body’s natural defenses against oxidative stress, inflammation, and DNA damage. In addition, the chemical later was found to improve the body’s heat-shock response, a cascade of events used to protect cells from the stress caused by high temperatures, including those experienced when people have fever.

About one-half of parents report that their children’s autistic behavior improves noticeably when they have a fever, then reverts back when the fever is gone. In 2007, Dr. Zimmerman tested this anecdotal trend clinically and found it to be true, though a mechanism for the fever effect was not identified. Because fevers, similar to sulforaphane, initiate the body’s heat-shock response, Drs. Zimmerman and Talalay wondered if sulforaphane could cause the same temporary improvement in autism that fevers do.

Improvement Linked to Sulforaphane
Before the start of the trial, the patients’ caregivers and physicians filled out three standard behavioral assessments—the Aberrant Behavior Checklist (ABC), the Social Responsiveness Scale (SRS), and the Clinical Global Impressions-Improvement scale (CGI-I). The assessments measure sensory sensitivities, ability to relate to others, verbal communication skills, social interactions, and other behaviors related to autism. Twenty-six participants were randomly selected to receive, based on their weight, 9 to 27 mg of sulforaphane daily, and 14 received placebo. Behavioral assessments were again completed at four, 10, and 18 weeks while treatment continued. A final assessment was completed for most of the participants four weeks after the treatment had stopped.

Most subjects who responded to sulforaphane showed significant improvements by the first measurement at four weeks and continued to improve during the rest of the treatment. After 18 weeks of treatment, the average ABC and SRS scores of those who received sulforaphane had decreased 34% and 17%, respectively, with improvements in bouts of irritability, lethargy, repetitive movements, hyperactivity, awareness, communication, motivation, and mannerisms.

After 18 weeks of treatment, according to the CGI-I scale, 46%, 54%, and 42% of sulforaphane recipients experienced noticeable improvements in social interaction, aberrant behaviors, and verbal communication, respectively.

Dr. Talalay noted that the scores of those who took sulforaphane trended back toward their original values after they stopped taking the chemical, similar to what happens to those who experience improvements during a fever. “It seems like sulforaphane is temporarily helping cells to cope with their handicaps,” he said.

Dr. Zimmerman added that before his group learned which subjects received the sulforaphane or placebo, the impressions of the clinical team, including parents, were that 13 participants noticeably improved. For example, some treated subjects looked them in the eye and shook their hands, which they had not done before. They found out later that all 13 had been taking sulforaphane, which is half of the treatment group. Dr. Talalay cautioned that the levels of sulforaphane precursors present in different varieties of broccoli are highly variable. Furthermore, the capacity of individuals to convert these precursors to active sulforaphane also varies greatly. It would be difficult, he noted, to achieve the levels of sulforaphane used in this study by eating large amounts of broccoli or other cruciferous vegetables.

COLUMBUS, OHIO—Cognitive impairment at age 12 months predicts a subsequent diagnosis of autism spectrum disorder in children with tuberous sclerosis complex, according to researchers.

The relationship between intellectual disability and social-communication deficits among children with tuberous sclerosis complex, however, requires further investigation, said the investigators.

Shafali S. Jeste, MD, Assistant Professor in Psychiatry and Neurology at the University of California, Los Angeles, and colleagues conducted a longitudinal cohort study of infants with tuberous sclerosis complex to determine early clinical predictors of autism spectrum disorder and characterize the phenotype of autism in young children with tuberous sclerosis complex.

The researchers recruited infants with tuberous sclerosis complex and typically developing infants as young as 3 months and followed them longitudinally until age 36 months. They gathered data including standard cognitive and social-communication measures (ie, Mullen Scales of Early Learning, Autism Observation Scale of Infancy, and the Early Social Communication Scales), comorbidities questionnaires, and a detailed seizure history. Autism spectrum diagnosis was made using the Autism Diagnostic Observation Schedule and confirmed using best clinical estimate at ages 18, 24, and 36 months.

Of a population of 40 infants, 22 received a diagnosis of autism spectrum disorder. Children with autism had significantly greater cognitive delays by age 12 months and a significant decline in nonverbal IQ from ages 12 to 36 months, compared with children without autism. At 24 months, children with autism had significantly greater cognitive impairment, higher anxiety symptoms, more sleep impairment, and a trend toward greater seizure severity. Children not diagnosed with autism had subclinical evidence of social-communication impairment, particularly in language and play.

Do rTMS and Constraint Therapy Reduce Perinatal Stroke Hemiparesis?
Children with hemiparesis resulting from perinatal stroke perceive marked increases in goal-specific function following treatment with repetitive transcranial magnetic stimulation (rTMS) and constraint therapy, investigators reported.

Further study of noninvasive brain stimulation is feasible and may enhance motor learning therapy in such patients, according to the researchers.

Researchers previously had studied rTMS and constraint therapy in adults with stroke, but the treatments had not been examined in perinatal stroke. Adam Kirton, MD, Associate Professor of Pediatrics and Clinical Neurosciences at the University of Calgary in Canada, and colleagues conducted a blinded factorial trial of rTMS and constraint therapy in 45 children with perinatal stroke hemiparesis. Eligible participants were between ages 6 and 18, and the sample’s mean age was 11.

The children were randomized to daily inhibitory rTMS (ie, 1,200 stimulations at 1 Hz) over contralesional M1, constraint therapy, both treatments, or neither treatment. All interventions were administered for two weeks as part of a goal-directed, peer-supported motor learning camp.

The study’s primary outcome measure was the Canadian Occupational Performance Measure (COPM) at one, eight, and 24 weeks. Secondary outcomes included Assisting Hand Assessment (AHA), Melbourne Assessment (MA), safety, and tolerability. The researchers assessed change across treatment groups from baseline to six months and across all time points.

For all participants, COPM performance and satisfaction scores increased, and maximal gains were observed at six months. Linear mixed effects model analysis demonstrated effects of combined rTMS and constraint therapy on AHA gains at all time points. Constraint therapy alone increased AHA at two months, rTMS alone increased AHA at one week, and neither treatment decreased normal hand function. Affected hand function did not decrease with rTMS in children with ipsilateral corticospinal tract arrangements. The procedures were well tolerated.

Arbaclofen May Not Reduce Social Avoidance in Fragile X Syndrome
Arbaclofen may not reduce social avoidance among patients with fragile X syndrome, according to clinical trial results presented. The drug may modify the disease’s trajectory, however, and deserves further testing, said Elizabeth Berry-Kravis, MD, PhD.

Arbaclofen is a specific GABA-B agonist that has been approved to treat spasticity in multiple sclerosis. The drug improved several abnormal phenotypes in animal models of fragile X syndrome and showed promise in a phase II clinical trial. Dr. Berry-Kravis, Associate Professor of Biochemistry, Neurological Sciences, and Pediatrics at Rush Medical College in Chicago, and colleagues conducted two phase III placebo-controlled trials to determine the drug’s safety and efficacy for social avoidance in fragile X syndrome.

The investigators randomized 125 patients to arbaclofen or placebo in a flexible-dose trial. Eligible patients were between ages 12 and 50. In a separate fixed-dose trial, the researchers randomized 172 participants to 5 mg of arbaclofen twice per day, 10 mg of arbaclofen twice per day, 10 mg of arbaclofen three times per day, or placebo. Eligible subjects in this trial were between ages 5 and 11.

The primary end point for both trials was the Fragile X Syndrome Social Avoidance subscale of the Aberrant Behavior Checklist (ABC). Secondary outcomes included other ABC subscale scores, Clinical Global Impression–Improvement score, Clinical Global Impression-Severity score, and Vineland Socialization domain score.

 

The investigators observed no serious adverse events during the trial. The most common adverse events included headache, vomiting, nausea, irritability, anxiety, hyperactivity, decreased appetite, and infections. In all, 12 patients discontinued participation in the trial because of neurobehavioral adverse events.

The flexible-dose trial did not indicate a benefit for arbaclofen over placebo for any outcome. The highest dose group in the fixed-dose trial had significantly better outcome than those who received placebo on the ABC Fragile X Irritability subscale. The same group demonstrated a trend toward benefit on the ABC Fragile X Social Avoidance and Hyperactivity subscales.

“Data from secondary measures and the long-term treatment extension (improved Vineland Socialization [domain score]) suggest that some patients derive benefit, but these studies illustrate the challenges of translating targeted treatments from animal models to humans in fragile X syndrome,” said Dr. Berry-Kravis.

Everolimus Reduces SEGA Volume in Tuberous Sclerosis Complex
Everolimus, an mTOR inhibitor, significantly reduces the volume of subependymal giant cell astrocytoma (SEGA) in children with tuberous sclerosis complex, according to an extension analysis presented. In a phase III trial, the researchers did not find any new safety concerns to be associated with the drug.

David N. Franz, MD, Pediatric Neurologist at Cincinnati Children’s Hospital Medical Center, and colleagues enrolled 117 patients in a randomized, double-blind trial of everolimus. All patients had SEGA associated with tuberous sclerosis complex of at least 1 cm in diameter. Participants received either 4.5 mg/m2/day of oral everolimus or placebo. The primary end point was SEGA response rate, which the investigators defined as the proportion of patients with 50% or greater reduction in SEGA volume, compared with baseline.

Patients’ mean age was approximately 11, and mean SEGA volume was 2.6 cm³. Participants received treatment for a median of 41 months.

At the original cutoff of the trial, SEGA response rate was 34.6% for everolimus and 0.0% for placebo. At that point, patients on placebo were offered open-label everolimus in the extension phase of the trial. As of January 11, 2013, 111 patients had received at least one dose of everolimus and were included in the extension analysis. The overall SEGA response rate was 48.6%, and the SEGA response rate for everolimus increased steadily until week 96. The duration of SEGA response ranged from 2.1 to 31.1 months.

Adverse events were common, but their incidence decreased with time. Approximately 40% of patients had serious adverse events, and 19% were suspected to be associated with everolimus. The most frequent serious adverse events occurring in more than 3% of patients were pneumonia, pyrexia, gastroenteritis, and convulsion.

—Erik Greb

COLUMBUS, OHIO—Cognitive impairment at age 12 months predicts a subsequent diagnosis of autism spectrum disorder in children with tuberous sclerosis complex, according to researchers.

The relationship between intellectual disability and social-communication deficits among children with tuberous sclerosis complex, however, requires further investigation, said the investigators.

Shafali S. Jeste, MD, Assistant Professor in Psychiatry and Neurology at the University of California, Los Angeles, and colleagues conducted a longitudinal cohort study of infants with tuberous sclerosis complex to determine early clinical predictors of autism spectrum disorder and characterize the phenotype of autism in young children with tuberous sclerosis complex.

The researchers recruited infants with tuberous sclerosis complex and typically developing infants as young as 3 months and followed them longitudinally until age 36 months. They gathered data including standard cognitive and social-communication measures (ie, Mullen Scales of Early Learning, Autism Observation Scale of Infancy, and the Early Social Communication Scales), comorbidities questionnaires, and a detailed seizure history. Autism spectrum diagnosis was made using the Autism Diagnostic Observation Schedule and confirmed using best clinical estimate at ages 18, 24, and 36 months.

Of a population of 40 infants, 22 received a diagnosis of autism spectrum disorder. Children with autism had significantly greater cognitive delays by age 12 months and a significant decline in nonverbal IQ from ages 12 to 36 months, compared with children without autism. At 24 months, children with autism had significantly greater cognitive impairment, higher anxiety symptoms, more sleep impairment, and a trend toward greater seizure severity. Children not diagnosed with autism had subclinical evidence of social-communication impairment, particularly in language and play.

Do rTMS and Constraint Therapy Reduce Perinatal Stroke Hemiparesis?
Children with hemiparesis resulting from perinatal stroke perceive marked increases in goal-specific function following treatment with repetitive transcranial magnetic stimulation (rTMS) and constraint therapy, investigators reported.

Further study of noninvasive brain stimulation is feasible and may enhance motor learning therapy in such patients, according to the researchers.

Researchers previously had studied rTMS and constraint therapy in adults with stroke, but the treatments had not been examined in perinatal stroke. Adam Kirton, MD, Associate Professor of Pediatrics and Clinical Neurosciences at the University of Calgary in Canada, and colleagues conducted a blinded factorial trial of rTMS and constraint therapy in 45 children with perinatal stroke hemiparesis. Eligible participants were between ages 6 and 18, and the sample’s mean age was 11.

The children were randomized to daily inhibitory rTMS (ie, 1,200 stimulations at 1 Hz) over contralesional M1, constraint therapy, both treatments, or neither treatment. All interventions were administered for two weeks as part of a goal-directed, peer-supported motor learning camp.

The study’s primary outcome measure was the Canadian Occupational Performance Measure (COPM) at one, eight, and 24 weeks. Secondary outcomes included Assisting Hand Assessment (AHA), Melbourne Assessment (MA), safety, and tolerability. The researchers assessed change across treatment groups from baseline to six months and across all time points.

For all participants, COPM performance and satisfaction scores increased, and maximal gains were observed at six months. Linear mixed effects model analysis demonstrated effects of combined rTMS and constraint therapy on AHA gains at all time points. Constraint therapy alone increased AHA at two months, rTMS alone increased AHA at one week, and neither treatment decreased normal hand function. Affected hand function did not decrease with rTMS in children with ipsilateral corticospinal tract arrangements. The procedures were well tolerated.

Arbaclofen May Not Reduce Social Avoidance in Fragile X Syndrome
Arbaclofen may not reduce social avoidance among patients with fragile X syndrome, according to clinical trial results presented. The drug may modify the disease’s trajectory, however, and deserves further testing, said Elizabeth Berry-Kravis, MD, PhD.

Arbaclofen is a specific GABA-B agonist that has been approved to treat spasticity in multiple sclerosis. The drug improved several abnormal phenotypes in animal models of fragile X syndrome and showed promise in a phase II clinical trial. Dr. Berry-Kravis, Associate Professor of Biochemistry, Neurological Sciences, and Pediatrics at Rush Medical College in Chicago, and colleagues conducted two phase III placebo-controlled trials to determine the drug’s safety and efficacy for social avoidance in fragile X syndrome.

The investigators randomized 125 patients to arbaclofen or placebo in a flexible-dose trial. Eligible patients were between ages 12 and 50. In a separate fixed-dose trial, the researchers randomized 172 participants to 5 mg of arbaclofen twice per day, 10 mg of arbaclofen twice per day, 10 mg of arbaclofen three times per day, or placebo. Eligible subjects in this trial were between ages 5 and 11.

The primary end point for both trials was the Fragile X Syndrome Social Avoidance subscale of the Aberrant Behavior Checklist (ABC). Secondary outcomes included other ABC subscale scores, Clinical Global Impression–Improvement score, Clinical Global Impression-Severity score, and Vineland Socialization domain score.

 

The investigators observed no serious adverse events during the trial. The most common adverse events included headache, vomiting, nausea, irritability, anxiety, hyperactivity, decreased appetite, and infections. In all, 12 patients discontinued participation in the trial because of neurobehavioral adverse events.

The flexible-dose trial did not indicate a benefit for arbaclofen over placebo for any outcome. The highest dose group in the fixed-dose trial had significantly better outcome than those who received placebo on the ABC Fragile X Irritability subscale. The same group demonstrated a trend toward benefit on the ABC Fragile X Social Avoidance and Hyperactivity subscales.

“Data from secondary measures and the long-term treatment extension (improved Vineland Socialization [domain score]) suggest that some patients derive benefit, but these studies illustrate the challenges of translating targeted treatments from animal models to humans in fragile X syndrome,” said Dr. Berry-Kravis.

Everolimus Reduces SEGA Volume in Tuberous Sclerosis Complex
Everolimus, an mTOR inhibitor, significantly reduces the volume of subependymal giant cell astrocytoma (SEGA) in children with tuberous sclerosis complex, according to an extension analysis presented. In a phase III trial, the researchers did not find any new safety concerns to be associated with the drug.

David N. Franz, MD, Pediatric Neurologist at Cincinnati Children’s Hospital Medical Center, and colleagues enrolled 117 patients in a randomized, double-blind trial of everolimus. All patients had SEGA associated with tuberous sclerosis complex of at least 1 cm in diameter. Participants received either 4.5 mg/m2/day of oral everolimus or placebo. The primary end point was SEGA response rate, which the investigators defined as the proportion of patients with 50% or greater reduction in SEGA volume, compared with baseline.

Patients’ mean age was approximately 11, and mean SEGA volume was 2.6 cm³. Participants received treatment for a median of 41 months.

At the original cutoff of the trial, SEGA response rate was 34.6% for everolimus and 0.0% for placebo. At that point, patients on placebo were offered open-label everolimus in the extension phase of the trial. As of January 11, 2013, 111 patients had received at least one dose of everolimus and were included in the extension analysis. The overall SEGA response rate was 48.6%, and the SEGA response rate for everolimus increased steadily until week 96. The duration of SEGA response ranged from 2.1 to 31.1 months.

Adverse events were common, but their incidence decreased with time. Approximately 40% of patients had serious adverse events, and 19% were suspected to be associated with everolimus. The most frequent serious adverse events occurring in more than 3% of patients were pneumonia, pyrexia, gastroenteritis, and convulsion.

—Erik Greb

COLUMBUS, OHIO—Cognitive impairment at age 12 months predicts a subsequent diagnosis of autism spectrum disorder in children with tuberous sclerosis complex, according to researchers.

The relationship between intellectual disability and social-communication deficits among children with tuberous sclerosis complex, however, requires further investigation, said the investigators.

Shafali S. Jeste, MD, Assistant Professor in Psychiatry and Neurology at the University of California, Los Angeles, and colleagues conducted a longitudinal cohort study of infants with tuberous sclerosis complex to determine early clinical predictors of autism spectrum disorder and characterize the phenotype of autism in young children with tuberous sclerosis complex.

The researchers recruited infants with tuberous sclerosis complex and typically developing infants as young as 3 months and followed them longitudinally until age 36 months. They gathered data including standard cognitive and social-communication measures (ie, Mullen Scales of Early Learning, Autism Observation Scale of Infancy, and the Early Social Communication Scales), comorbidities questionnaires, and a detailed seizure history. Autism spectrum diagnosis was made using the Autism Diagnostic Observation Schedule and confirmed using best clinical estimate at ages 18, 24, and 36 months.

Of a population of 40 infants, 22 received a diagnosis of autism spectrum disorder. Children with autism had significantly greater cognitive delays by age 12 months and a significant decline in nonverbal IQ from ages 12 to 36 months, compared with children without autism. At 24 months, children with autism had significantly greater cognitive impairment, higher anxiety symptoms, more sleep impairment, and a trend toward greater seizure severity. Children not diagnosed with autism had subclinical evidence of social-communication impairment, particularly in language and play.

Do rTMS and Constraint Therapy Reduce Perinatal Stroke Hemiparesis?
Children with hemiparesis resulting from perinatal stroke perceive marked increases in goal-specific function following treatment with repetitive transcranial magnetic stimulation (rTMS) and constraint therapy, investigators reported.

Further study of noninvasive brain stimulation is feasible and may enhance motor learning therapy in such patients, according to the researchers.

Researchers previously had studied rTMS and constraint therapy in adults with stroke, but the treatments had not been examined in perinatal stroke. Adam Kirton, MD, Associate Professor of Pediatrics and Clinical Neurosciences at the University of Calgary in Canada, and colleagues conducted a blinded factorial trial of rTMS and constraint therapy in 45 children with perinatal stroke hemiparesis. Eligible participants were between ages 6 and 18, and the sample’s mean age was 11.

The children were randomized to daily inhibitory rTMS (ie, 1,200 stimulations at 1 Hz) over contralesional M1, constraint therapy, both treatments, or neither treatment. All interventions were administered for two weeks as part of a goal-directed, peer-supported motor learning camp.

The study’s primary outcome measure was the Canadian Occupational Performance Measure (COPM) at one, eight, and 24 weeks. Secondary outcomes included Assisting Hand Assessment (AHA), Melbourne Assessment (MA), safety, and tolerability. The researchers assessed change across treatment groups from baseline to six months and across all time points.

For all participants, COPM performance and satisfaction scores increased, and maximal gains were observed at six months. Linear mixed effects model analysis demonstrated effects of combined rTMS and constraint therapy on AHA gains at all time points. Constraint therapy alone increased AHA at two months, rTMS alone increased AHA at one week, and neither treatment decreased normal hand function. Affected hand function did not decrease with rTMS in children with ipsilateral corticospinal tract arrangements. The procedures were well tolerated.

Arbaclofen May Not Reduce Social Avoidance in Fragile X Syndrome
Arbaclofen may not reduce social avoidance among patients with fragile X syndrome, according to clinical trial results presented. The drug may modify the disease’s trajectory, however, and deserves further testing, said Elizabeth Berry-Kravis, MD, PhD.

Arbaclofen is a specific GABA-B agonist that has been approved to treat spasticity in multiple sclerosis. The drug improved several abnormal phenotypes in animal models of fragile X syndrome and showed promise in a phase II clinical trial. Dr. Berry-Kravis, Associate Professor of Biochemistry, Neurological Sciences, and Pediatrics at Rush Medical College in Chicago, and colleagues conducted two phase III placebo-controlled trials to determine the drug’s safety and efficacy for social avoidance in fragile X syndrome.

The investigators randomized 125 patients to arbaclofen or placebo in a flexible-dose trial. Eligible patients were between ages 12 and 50. In a separate fixed-dose trial, the researchers randomized 172 participants to 5 mg of arbaclofen twice per day, 10 mg of arbaclofen twice per day, 10 mg of arbaclofen three times per day, or placebo. Eligible subjects in this trial were between ages 5 and 11.

The primary end point for both trials was the Fragile X Syndrome Social Avoidance subscale of the Aberrant Behavior Checklist (ABC). Secondary outcomes included other ABC subscale scores, Clinical Global Impression–Improvement score, Clinical Global Impression-Severity score, and Vineland Socialization domain score.

 

The investigators observed no serious adverse events during the trial. The most common adverse events included headache, vomiting, nausea, irritability, anxiety, hyperactivity, decreased appetite, and infections. In all, 12 patients discontinued participation in the trial because of neurobehavioral adverse events.

The flexible-dose trial did not indicate a benefit for arbaclofen over placebo for any outcome. The highest dose group in the fixed-dose trial had significantly better outcome than those who received placebo on the ABC Fragile X Irritability subscale. The same group demonstrated a trend toward benefit on the ABC Fragile X Social Avoidance and Hyperactivity subscales.

“Data from secondary measures and the long-term treatment extension (improved Vineland Socialization [domain score]) suggest that some patients derive benefit, but these studies illustrate the challenges of translating targeted treatments from animal models to humans in fragile X syndrome,” said Dr. Berry-Kravis.

Everolimus Reduces SEGA Volume in Tuberous Sclerosis Complex
Everolimus, an mTOR inhibitor, significantly reduces the volume of subependymal giant cell astrocytoma (SEGA) in children with tuberous sclerosis complex, according to an extension analysis presented. In a phase III trial, the researchers did not find any new safety concerns to be associated with the drug.

David N. Franz, MD, Pediatric Neurologist at Cincinnati Children’s Hospital Medical Center, and colleagues enrolled 117 patients in a randomized, double-blind trial of everolimus. All patients had SEGA associated with tuberous sclerosis complex of at least 1 cm in diameter. Participants received either 4.5 mg/m2/day of oral everolimus or placebo. The primary end point was SEGA response rate, which the investigators defined as the proportion of patients with 50% or greater reduction in SEGA volume, compared with baseline.

Patients’ mean age was approximately 11, and mean SEGA volume was 2.6 cm³. Participants received treatment for a median of 41 months.

At the original cutoff of the trial, SEGA response rate was 34.6% for everolimus and 0.0% for placebo. At that point, patients on placebo were offered open-label everolimus in the extension phase of the trial. As of January 11, 2013, 111 patients had received at least one dose of everolimus and were included in the extension analysis. The overall SEGA response rate was 48.6%, and the SEGA response rate for everolimus increased steadily until week 96. The duration of SEGA response ranged from 2.1 to 31.1 months.

Adverse events were common, but their incidence decreased with time. Approximately 40% of patients had serious adverse events, and 19% were suspected to be associated with everolimus. The most frequent serious adverse events occurring in more than 3% of patients were pneumonia, pyrexia, gastroenteritis, and convulsion.

—Erik Greb

Autism may begin in utero, according to a study of postmortem brain tissue from children with and without autism published online ahead of print March 27 in the New England Journal of Medicine.

The findings imply that layer formation and layer-specific neuronal differentiation are dysregulated during prenatal development. The study also suggests that early recognition and treatment of autism may allow the developing brains of autistic children to construct alternative brain pathways around the patchy defects in the cortex. The result could be improved social functioning and communication, the researchers theorized.

Researchers used gene expression to examine cellular markers in each of the cortical layers, as well as genes that are associated with autism. Markers for several layers of the cortex were absent in the brain tissue of 10 of 11 (91%) children with autism and in one of 11 (9%) control children. The areas of disorganization were seen in multiple cortical layers, with most abnormal expression noted in layers 4 and 5 and focal disruption of cortical laminar architecture as patches that were 5 to 7 mm long.

—Mary Jo M. Dales

Autism may begin in utero, according to a study of postmortem brain tissue from children with and without autism published online ahead of print March 27 in the New England Journal of Medicine.

The findings imply that layer formation and layer-specific neuronal differentiation are dysregulated during prenatal development. The study also suggests that early recognition and treatment of autism may allow the developing brains of autistic children to construct alternative brain pathways around the patchy defects in the cortex. The result could be improved social functioning and communication, the researchers theorized.

Researchers used gene expression to examine cellular markers in each of the cortical layers, as well as genes that are associated with autism. Markers for several layers of the cortex were absent in the brain tissue of 10 of 11 (91%) children with autism and in one of 11 (9%) control children. The areas of disorganization were seen in multiple cortical layers, with most abnormal expression noted in layers 4 and 5 and focal disruption of cortical laminar architecture as patches that were 5 to 7 mm long.

—Mary Jo M. Dales

Autism may begin in utero, according to a study of postmortem brain tissue from children with and without autism published online ahead of print March 27 in the New England Journal of Medicine.

The findings imply that layer formation and layer-specific neuronal differentiation are dysregulated during prenatal development. The study also suggests that early recognition and treatment of autism may allow the developing brains of autistic children to construct alternative brain pathways around the patchy defects in the cortex. The result could be improved social functioning and communication, the researchers theorized.

Researchers used gene expression to examine cellular markers in each of the cortical layers, as well as genes that are associated with autism. Markers for several layers of the cortex were absent in the brain tissue of 10 of 11 (91%) children with autism and in one of 11 (9%) control children. The areas of disorganization were seen in multiple cortical layers, with most abnormal expression noted in layers 4 and 5 and focal disruption of cortical laminar architecture as patches that were 5 to 7 mm long.

—Mary Jo M. Dales

The CDC estimates that about one in 68 US children has autism spectrum disorder, according to findings published in the March 28 issue of Morbidity and Mortality Weekly Report Surveillance Summaries. This prevalence is a 30% increase from the CDC’s estimate of one in 88 children using 2008 data.

The findings also show that autism spectrum disorder continues to be more prevalent in boys than in girls: one in 42 boys had autism spectrum disorder in the latest report, compared with one in 189 girls.

The increased prevalence could be attributed to improved clinician identification of autism, a growing number of autistic children with average to above-average intellectual ability, or a combination of both factors, said Coleen Boyle, PhD, Director of the CDC’s National Center on Birth Defects and Developmental Disabilities (NCBDDD).

The CDC analyzed 2010 data collected by its Autism and Developmental Disabilities Monitoring (ADDM) Network, which provides population-based estimates of autism spectrum disorder prevalence in children age 8 at 11 sites in the United States based on records from community sources that diagnose and provide services to children with developmental disabilities.

Of the 11 sites studied, seven had information available on the intellectual ability of at least 70% of children with autism spectrum disorder. Of the 3,604 children for whom data were available, 31% were classified as having intellectual disability (IQ of 70 or lower), 23% were considered borderline (IQ = 71 to 85), and 46% had IQ scores of greater than 85, considered average or above average intellectual ability.

“We recognize now that autism is a spectrum, no longer limited to the severely affected,” said Marshalyn Yeargin-Allsopp, MD, Chief of the Developmental Disabilities branch of NCBDDD. “There are children with higher IQs being diagnosed who may not even be receiving special education services, and the numbers may reflect that.”

Non-Hispanic white children were 30% more likely to be diagnosed with autism spectrum disorder than were non-Hispanic black children and about 50% more likely to be diagnosed with autism spectrum disorder than were Hispanic children.

Dr. Boyle stressed the importance of early screening and identification of autism spectrum disorder in children (it can be diagnosed by the time a child reaches age 2) and urged parents to take action if a child shows any signs of developmental delays.

“Community leaders, health professionals, educators, and childcare providers should use these data to ensure that children with autism spectrum disorder are identified as early as possible and connected to the services they need,” said Dr. Boyle.

To help promote early intervention in autism spectrum disorder, the CDC will be launching an awareness initiative called “Birth to Five, Watch Me Thrive,” which aims to provide parents, teachers, and community members with information and resources about developmental milestones and screening for autism.

“Most children with autism are not diagnosed until after age 4,” said Dr. Boyle. “The CDC will continue to promote early identification and research. The earlier a child is identified and connected with services, the better.”

The CDC cited several limitations to the report. First, the surveillance sites were not selected to be representative of the entire United States. Second, population denominators used for this report were based on the 2010 decennial census. Comparisons with previous ADDM findings thus should be interpreted with caution because ADDM reports from nondecennial surveillance years are likely influenced by greater error in the population denominators used for those previous surveillance years, which were based on postcensus estimates. Third, three of the nine sites with access to review children’s education records did not receive permission to do so in all school districts within the site’s overall surveillance area. Fourth, findings that address intellectual ability might not be generalizable to all ADDM sites. Finally, race and ethnicity are presented in broad terms and should not be interpreted as generalizable to all persons within those categories.

—Madhu Rajaraman

The CDC estimates that about one in 68 US children has autism spectrum disorder, according to findings published in the March 28 issue of Morbidity and Mortality Weekly Report Surveillance Summaries. This prevalence is a 30% increase from the CDC’s estimate of one in 88 children using 2008 data.

The findings also show that autism spectrum disorder continues to be more prevalent in boys than in girls: one in 42 boys had autism spectrum disorder in the latest report, compared with one in 189 girls.

The increased prevalence could be attributed to improved clinician identification of autism, a growing number of autistic children with average to above-average intellectual ability, or a combination of both factors, said Coleen Boyle, PhD, Director of the CDC’s National Center on Birth Defects and Developmental Disabilities (NCBDDD).

The CDC analyzed 2010 data collected by its Autism and Developmental Disabilities Monitoring (ADDM) Network, which provides population-based estimates of autism spectrum disorder prevalence in children age 8 at 11 sites in the United States based on records from community sources that diagnose and provide services to children with developmental disabilities.

Of the 11 sites studied, seven had information available on the intellectual ability of at least 70% of children with autism spectrum disorder. Of the 3,604 children for whom data were available, 31% were classified as having intellectual disability (IQ of 70 or lower), 23% were considered borderline (IQ = 71 to 85), and 46% had IQ scores of greater than 85, considered average or above average intellectual ability.

“We recognize now that autism is a spectrum, no longer limited to the severely affected,” said Marshalyn Yeargin-Allsopp, MD, Chief of the Developmental Disabilities branch of NCBDDD. “There are children with higher IQs being diagnosed who may not even be receiving special education services, and the numbers may reflect that.”

Non-Hispanic white children were 30% more likely to be diagnosed with autism spectrum disorder than were non-Hispanic black children and about 50% more likely to be diagnosed with autism spectrum disorder than were Hispanic children.

Dr. Boyle stressed the importance of early screening and identification of autism spectrum disorder in children (it can be diagnosed by the time a child reaches age 2) and urged parents to take action if a child shows any signs of developmental delays.

“Community leaders, health professionals, educators, and childcare providers should use these data to ensure that children with autism spectrum disorder are identified as early as possible and connected to the services they need,” said Dr. Boyle.

To help promote early intervention in autism spectrum disorder, the CDC will be launching an awareness initiative called “Birth to Five, Watch Me Thrive,” which aims to provide parents, teachers, and community members with information and resources about developmental milestones and screening for autism.

“Most children with autism are not diagnosed until after age 4,” said Dr. Boyle. “The CDC will continue to promote early identification and research. The earlier a child is identified and connected with services, the better.”

The CDC cited several limitations to the report. First, the surveillance sites were not selected to be representative of the entire United States. Second, population denominators used for this report were based on the 2010 decennial census. Comparisons with previous ADDM findings thus should be interpreted with caution because ADDM reports from nondecennial surveillance years are likely influenced by greater error in the population denominators used for those previous surveillance years, which were based on postcensus estimates. Third, three of the nine sites with access to review children’s education records did not receive permission to do so in all school districts within the site’s overall surveillance area. Fourth, findings that address intellectual ability might not be generalizable to all ADDM sites. Finally, race and ethnicity are presented in broad terms and should not be interpreted as generalizable to all persons within those categories.

—Madhu Rajaraman

The CDC estimates that about one in 68 US children has autism spectrum disorder, according to findings published in the March 28 issue of Morbidity and Mortality Weekly Report Surveillance Summaries. This prevalence is a 30% increase from the CDC’s estimate of one in 88 children using 2008 data.

The findings also show that autism spectrum disorder continues to be more prevalent in boys than in girls: one in 42 boys had autism spectrum disorder in the latest report, compared with one in 189 girls.

The increased prevalence could be attributed to improved clinician identification of autism, a growing number of autistic children with average to above-average intellectual ability, or a combination of both factors, said Coleen Boyle, PhD, Director of the CDC’s National Center on Birth Defects and Developmental Disabilities (NCBDDD).

The CDC analyzed 2010 data collected by its Autism and Developmental Disabilities Monitoring (ADDM) Network, which provides population-based estimates of autism spectrum disorder prevalence in children age 8 at 11 sites in the United States based on records from community sources that diagnose and provide services to children with developmental disabilities.

Of the 11 sites studied, seven had information available on the intellectual ability of at least 70% of children with autism spectrum disorder. Of the 3,604 children for whom data were available, 31% were classified as having intellectual disability (IQ of 70 or lower), 23% were considered borderline (IQ = 71 to 85), and 46% had IQ scores of greater than 85, considered average or above average intellectual ability.

“We recognize now that autism is a spectrum, no longer limited to the severely affected,” said Marshalyn Yeargin-Allsopp, MD, Chief of the Developmental Disabilities branch of NCBDDD. “There are children with higher IQs being diagnosed who may not even be receiving special education services, and the numbers may reflect that.”

Non-Hispanic white children were 30% more likely to be diagnosed with autism spectrum disorder than were non-Hispanic black children and about 50% more likely to be diagnosed with autism spectrum disorder than were Hispanic children.

Dr. Boyle stressed the importance of early screening and identification of autism spectrum disorder in children (it can be diagnosed by the time a child reaches age 2) and urged parents to take action if a child shows any signs of developmental delays.

“Community leaders, health professionals, educators, and childcare providers should use these data to ensure that children with autism spectrum disorder are identified as early as possible and connected to the services they need,” said Dr. Boyle.

To help promote early intervention in autism spectrum disorder, the CDC will be launching an awareness initiative called “Birth to Five, Watch Me Thrive,” which aims to provide parents, teachers, and community members with information and resources about developmental milestones and screening for autism.

“Most children with autism are not diagnosed until after age 4,” said Dr. Boyle. “The CDC will continue to promote early identification and research. The earlier a child is identified and connected with services, the better.”

The CDC cited several limitations to the report. First, the surveillance sites were not selected to be representative of the entire United States. Second, population denominators used for this report were based on the 2010 decennial census. Comparisons with previous ADDM findings thus should be interpreted with caution because ADDM reports from nondecennial surveillance years are likely influenced by greater error in the population denominators used for those previous surveillance years, which were based on postcensus estimates. Third, three of the nine sites with access to review children’s education records did not receive permission to do so in all school districts within the site’s overall surveillance area. Fourth, findings that address intellectual ability might not be generalizable to all ADDM sites. Finally, race and ethnicity are presented in broad terms and should not be interpreted as generalizable to all persons within those categories.

—Madhu Rajaraman

Living in the stroke belt as an adolescent is significantly associated with a high risk of stroke, according to research published online ahead of print April 24 in Neurology. Researchers examined data for 24,544 stroke-free participants in the Reasons for Geographic and Racial Differences in Stroke study. Stroke belt exposure was calculated by combinations of stroke belt birthplace, current residence, and proportion of years in the stroke belt during discrete age categories. Risk of stroke was significantly associated with proportion of life in the stroke belt and with all other exposure periods except birth, ages 31 to 45, and current residence. After adjustment for risk factors, the risk of stroke remained significantly associated only with proportion of residence in the stroke belt during adolescence.

Increased levels of trimethylamine-N-oxide (TMAO), a proatherosclerotic metabolite, are associated with an increased risk of stroke, myocardial infarction, or death, according to research published in the April 25 New England Journal of Medicine. Investigators measured TMAO, choline, and betaine levels in patients who had eaten two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine before and after suppressing intestinal microbiota with antibiotics. They also examined the relationship between fasting plasma levels of TMAO and major adverse cardiovascular events during three years of follow-up. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event. An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors, as well as in lower-risk subgroups.

A single-nucleotide polymorphism (SNP) in the ABCA7 gene was significantly linked with an increased risk of Alzheimer’s disease among African Americans, according to research published in the April 10 JAMA. African Americans with this mutation have nearly double the risk of Alzheimer’s disease, but the SNP is not associated with the disease among Europeans. The effect size for the SNP in ABCA7 was comparable with that of the APOE ε4–determining SNP rs429358. Investigators examined data for 5,896 African Americans (1,968 with Alzheimer’s disease and 3,928 controls) who were 60 or older. Data were collected between 1989 and 2011 at multiple sites. The team assessed the association of Alzheimer’s disease with genotyped and imputed SNPs in case–control and in family-based data sets.

The FDA has approved the Precision Spectra Spinal Cord Stimulator (SCS) System, which is designed to provide improved pain relief to patients with chronic pain. The system, manufactured by Boston Scientific (Natick, Massachusetts), includes Illumina 3D software intended to improve physicians’ control of the stimulation field. It is based on a proprietary computer model that takes into account 3-D anatomical structures, including the conductivity of the spinal cord and surrounding tissue. The physician can select a desired location on the spinal cord and prompt the programming software to create a customized stimulation field to mask the patient’s pain. Previous SCS systems included 16 contacts, but the Precision Spectra system includes 32 contacts and is designed to offer more coverage of the spinal cord.

Framingham risk scores may be better than a dementia risk score for assessing individuals’ risk of cognitive decline and targeting modifiable risk factors, according to research published in the April 2 Neurology. Researchers examined data for participants in the Whitehall II longitudinal cohort study. Subjects’ mean age at baseline was 55.6. The investigators compared the Framingham general cardiovascular disease risk score and the Framingham stroke risk score with the Cardiovascular Risk Factors, Aging, and Dementia risk score. Patients underwent cognitive tests of reasoning, memory, verbal fluency, vocabulary, and global cognition three times over 10 years. Compared with the dementia risk score, cardiovascular and stroke risk scores showed slightly stronger associations with 10-year cognitive decline. The differences were statistically significant for semantic fluency and global cognitive scores.

Children born to women who used valproate during pregnancy may have a significantly increased risk of autism spectrum disorder and childhood autism, according to research published in the April 24 JAMA. Investigators used national registers to identify Danish children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders. The researchers analyzed the risks associated with all autism spectrum disorders, as well as childhood autism, and adjusted for potential confounders. The estimated absolute risk after 14 years of follow-up was 1.53% for autism spectrum disorder and 0.48% for childhood autism. The 508 children exposed to valproate had an absolute risk of 4.42% for autism spectrum disorder and an absolute risk of 2.50% for childhood autism. Results changed slightly after considering only the children born to women with epilepsy.

The antisense oligonucleotide ISIS 333611 is a safe treatment for amyotrophic lateral sclerosis (ALS), according to a trial published online ahead of print March 29 in Lancet Neurology. Investigators studied 32 patients with SOD1-positive ALS in a randomized, placebo-controlled, phase I trial. The researchers delivered the drug by intrathecal infusion using an external pump over 11.5 hours at increasing doses (0.15 mg, 0.50 mg, 1.50 mg, and 3.00 mg). Approximately 88% of patients in the placebo group had adverse events, compared with 83% in the active group. The most common events were post-lumbar puncture syndrome, back pain, and nausea. The investigators found no dose-limiting toxic effects or safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611.

 

Thalamic atrophy in patients with clinically isolated syndrome (CIS) is associated with the development of clinically definite multiple sclerosis (MS), according to a study published online ahead of print April 23 in Radiology. Using MRI, researchers assessed 216 patients with CIS at baseline, six months, one year, and two years. MRI measures of progression included new and enlarged T2 lesions and changes in whole-brain, tissue-specific global, and regional gray matter volumes. In mixed-effect model analysis, the lateral ventricle volume, accumulation of new total T2 and new enlarging T2 lesions increase, and thalamic and whole-brain volume decrease were associated with development of clinically definite MS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes were associated with the development of clinically definite MS.

Functional MRI (fMRI) can identify pain caused by heat in healthy persons, according to research published in the April 11 New England Journal of Medicine. In four studies of 114 participants, investigators developed an fMRI-based measure that predicts pain intensity, tested its sensitivity and specificity to pain versus warmth, assessed its specificity relative to social pain, and assessed the responsiveness of the measure to the analgesic remifentanil. The neurologic signature distinguished painful heat from nonpainful warmth, pain anticipation, and pain recall with sensitivity and specificity of 94% or more. The signature discriminated between painful heat and nonpainful warmth with 93% sensitivity and specificity. It also distinguished between physical pain and social pain with 85% sensitivity and 73% specificity. The strength of the signature response was substantially reduced after remifentanil administration.

Family history of late-onset Alzheimer’s disease is associated with an increased prevalence of an abnormal cerebral beta-amyloid and tau protein phenotype in patients with mild cognitive impairment (MCI), according to a study published on April 17 in PLOS One. Investigators studied 257 participants (ages 55 to 89) in the Alzheimer’s Disease Neuroimaging Initiative. Subjects were categorized as cognitively normal, having MCI, or having Alzheimer’s disease. Among patients with MCI, CSF Ab42 was lower, t-tau was higher, and t-tau–Ab42 ratio was higher in patients with a family history of Alzheimer’s disease than in patients without. A significant residual effect of family history on pathologic markers in MCI remained after adjusting for APOE e4. The effect of family history was not significant in patients with Alzheimer’s disease.

Most potential migraine triggers are so variable that it may not be possible to identify them without formal experimentation, according to a study published in the April issue of Headache. Investigators examined the similarity of day-to-day weather conditions over four years, as well as the similarity of ovarian hormones and perceived stress over a median of 89 days in nine patients with headache and regular menstrual cycles. A threshold of 90% similarity using Gower’s index identified similar days for comparison. The day-to-day variability in the three headache triggers was substantial enough that finding two naturally similar days for which to contrast the effect of a fourth trigger (eg, drinking wine) occurred infrequently. Fluctuations in weather patterns resulted in a median of 2.3 similar days each year.

Elevated low-density lipoprotein (LDL) cholesterol and altered cholesterol homeostasis may promote neurodegeneration, atherosclerosis, and Alzheimer’s disease by disrupting chromosome segregation, according to research published on April 12 in PLOS One. In a study of mice, investigators observed that high dietary cholesterol induced aneuploidy. In a separate study, the accumulation of intracellular cholesterol was associated with the accumulation of aneuploid fibroblasts, neurons, and glia in patients with Niemann-Pick C1. The researchers also observed that oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induced chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors. LDL-induced aneuploidy required the LDL receptor, but not Ab. Cholesterol treatment disrupted the structure of the mitotic spindle, providing a cell biologic mechanism for its aneugenic activity, and ethanol or calcium chelation attenuated lipoprotein-induced chromosome mis-segregation.

The incidence of dementia in central Stockholm may have decreased from the late 1980s to the early 2000s, according to research published online ahead of print April 17 in Neurology. Investigators analyzed data from two cross-sectional surveys of people ages 75 or older. One study was conducted from 1987 to 1989 and included 1,700 participants; the other was conducted from 2001 to 2004 and included 1,575 subjects. The team inferred the incidence of dementia according to its relationship with prevalence and survival. The adjusted odds ratio of dementia in the later study versus the earlier study was 1.17. The multiadjusted hazard ratio of death in the later study versus the earlier study was 0.71 in subjects with dementia, 0.68 in those without dementia, and 0.66 in all participants.

 

—Erik Greb
Senior Associate Editor

Living in the stroke belt as an adolescent is significantly associated with a high risk of stroke, according to research published online ahead of print April 24 in Neurology. Researchers examined data for 24,544 stroke-free participants in the Reasons for Geographic and Racial Differences in Stroke study. Stroke belt exposure was calculated by combinations of stroke belt birthplace, current residence, and proportion of years in the stroke belt during discrete age categories. Risk of stroke was significantly associated with proportion of life in the stroke belt and with all other exposure periods except birth, ages 31 to 45, and current residence. After adjustment for risk factors, the risk of stroke remained significantly associated only with proportion of residence in the stroke belt during adolescence.

Increased levels of trimethylamine-N-oxide (TMAO), a proatherosclerotic metabolite, are associated with an increased risk of stroke, myocardial infarction, or death, according to research published in the April 25 New England Journal of Medicine. Investigators measured TMAO, choline, and betaine levels in patients who had eaten two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine before and after suppressing intestinal microbiota with antibiotics. They also examined the relationship between fasting plasma levels of TMAO and major adverse cardiovascular events during three years of follow-up. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event. An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors, as well as in lower-risk subgroups.

A single-nucleotide polymorphism (SNP) in the ABCA7 gene was significantly linked with an increased risk of Alzheimer’s disease among African Americans, according to research published in the April 10 JAMA. African Americans with this mutation have nearly double the risk of Alzheimer’s disease, but the SNP is not associated with the disease among Europeans. The effect size for the SNP in ABCA7 was comparable with that of the APOE ε4–determining SNP rs429358. Investigators examined data for 5,896 African Americans (1,968 with Alzheimer’s disease and 3,928 controls) who were 60 or older. Data were collected between 1989 and 2011 at multiple sites. The team assessed the association of Alzheimer’s disease with genotyped and imputed SNPs in case–control and in family-based data sets.

The FDA has approved the Precision Spectra Spinal Cord Stimulator (SCS) System, which is designed to provide improved pain relief to patients with chronic pain. The system, manufactured by Boston Scientific (Natick, Massachusetts), includes Illumina 3D software intended to improve physicians’ control of the stimulation field. It is based on a proprietary computer model that takes into account 3-D anatomical structures, including the conductivity of the spinal cord and surrounding tissue. The physician can select a desired location on the spinal cord and prompt the programming software to create a customized stimulation field to mask the patient’s pain. Previous SCS systems included 16 contacts, but the Precision Spectra system includes 32 contacts and is designed to offer more coverage of the spinal cord.

Framingham risk scores may be better than a dementia risk score for assessing individuals’ risk of cognitive decline and targeting modifiable risk factors, according to research published in the April 2 Neurology. Researchers examined data for participants in the Whitehall II longitudinal cohort study. Subjects’ mean age at baseline was 55.6. The investigators compared the Framingham general cardiovascular disease risk score and the Framingham stroke risk score with the Cardiovascular Risk Factors, Aging, and Dementia risk score. Patients underwent cognitive tests of reasoning, memory, verbal fluency, vocabulary, and global cognition three times over 10 years. Compared with the dementia risk score, cardiovascular and stroke risk scores showed slightly stronger associations with 10-year cognitive decline. The differences were statistically significant for semantic fluency and global cognitive scores.

Children born to women who used valproate during pregnancy may have a significantly increased risk of autism spectrum disorder and childhood autism, according to research published in the April 24 JAMA. Investigators used national registers to identify Danish children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders. The researchers analyzed the risks associated with all autism spectrum disorders, as well as childhood autism, and adjusted for potential confounders. The estimated absolute risk after 14 years of follow-up was 1.53% for autism spectrum disorder and 0.48% for childhood autism. The 508 children exposed to valproate had an absolute risk of 4.42% for autism spectrum disorder and an absolute risk of 2.50% for childhood autism. Results changed slightly after considering only the children born to women with epilepsy.

The antisense oligonucleotide ISIS 333611 is a safe treatment for amyotrophic lateral sclerosis (ALS), according to a trial published online ahead of print March 29 in Lancet Neurology. Investigators studied 32 patients with SOD1-positive ALS in a randomized, placebo-controlled, phase I trial. The researchers delivered the drug by intrathecal infusion using an external pump over 11.5 hours at increasing doses (0.15 mg, 0.50 mg, 1.50 mg, and 3.00 mg). Approximately 88% of patients in the placebo group had adverse events, compared with 83% in the active group. The most common events were post-lumbar puncture syndrome, back pain, and nausea. The investigators found no dose-limiting toxic effects or safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611.

 

Thalamic atrophy in patients with clinically isolated syndrome (CIS) is associated with the development of clinically definite multiple sclerosis (MS), according to a study published online ahead of print April 23 in Radiology. Using MRI, researchers assessed 216 patients with CIS at baseline, six months, one year, and two years. MRI measures of progression included new and enlarged T2 lesions and changes in whole-brain, tissue-specific global, and regional gray matter volumes. In mixed-effect model analysis, the lateral ventricle volume, accumulation of new total T2 and new enlarging T2 lesions increase, and thalamic and whole-brain volume decrease were associated with development of clinically definite MS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes were associated with the development of clinically definite MS.

Functional MRI (fMRI) can identify pain caused by heat in healthy persons, according to research published in the April 11 New England Journal of Medicine. In four studies of 114 participants, investigators developed an fMRI-based measure that predicts pain intensity, tested its sensitivity and specificity to pain versus warmth, assessed its specificity relative to social pain, and assessed the responsiveness of the measure to the analgesic remifentanil. The neurologic signature distinguished painful heat from nonpainful warmth, pain anticipation, and pain recall with sensitivity and specificity of 94% or more. The signature discriminated between painful heat and nonpainful warmth with 93% sensitivity and specificity. It also distinguished between physical pain and social pain with 85% sensitivity and 73% specificity. The strength of the signature response was substantially reduced after remifentanil administration.

Family history of late-onset Alzheimer’s disease is associated with an increased prevalence of an abnormal cerebral beta-amyloid and tau protein phenotype in patients with mild cognitive impairment (MCI), according to a study published on April 17 in PLOS One. Investigators studied 257 participants (ages 55 to 89) in the Alzheimer’s Disease Neuroimaging Initiative. Subjects were categorized as cognitively normal, having MCI, or having Alzheimer’s disease. Among patients with MCI, CSF Ab42 was lower, t-tau was higher, and t-tau–Ab42 ratio was higher in patients with a family history of Alzheimer’s disease than in patients without. A significant residual effect of family history on pathologic markers in MCI remained after adjusting for APOE e4. The effect of family history was not significant in patients with Alzheimer’s disease.

Most potential migraine triggers are so variable that it may not be possible to identify them without formal experimentation, according to a study published in the April issue of Headache. Investigators examined the similarity of day-to-day weather conditions over four years, as well as the similarity of ovarian hormones and perceived stress over a median of 89 days in nine patients with headache and regular menstrual cycles. A threshold of 90% similarity using Gower’s index identified similar days for comparison. The day-to-day variability in the three headache triggers was substantial enough that finding two naturally similar days for which to contrast the effect of a fourth trigger (eg, drinking wine) occurred infrequently. Fluctuations in weather patterns resulted in a median of 2.3 similar days each year.

Elevated low-density lipoprotein (LDL) cholesterol and altered cholesterol homeostasis may promote neurodegeneration, atherosclerosis, and Alzheimer’s disease by disrupting chromosome segregation, according to research published on April 12 in PLOS One. In a study of mice, investigators observed that high dietary cholesterol induced aneuploidy. In a separate study, the accumulation of intracellular cholesterol was associated with the accumulation of aneuploid fibroblasts, neurons, and glia in patients with Niemann-Pick C1. The researchers also observed that oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induced chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors. LDL-induced aneuploidy required the LDL receptor, but not Ab. Cholesterol treatment disrupted the structure of the mitotic spindle, providing a cell biologic mechanism for its aneugenic activity, and ethanol or calcium chelation attenuated lipoprotein-induced chromosome mis-segregation.

The incidence of dementia in central Stockholm may have decreased from the late 1980s to the early 2000s, according to research published online ahead of print April 17 in Neurology. Investigators analyzed data from two cross-sectional surveys of people ages 75 or older. One study was conducted from 1987 to 1989 and included 1,700 participants; the other was conducted from 2001 to 2004 and included 1,575 subjects. The team inferred the incidence of dementia according to its relationship with prevalence and survival. The adjusted odds ratio of dementia in the later study versus the earlier study was 1.17. The multiadjusted hazard ratio of death in the later study versus the earlier study was 0.71 in subjects with dementia, 0.68 in those without dementia, and 0.66 in all participants.

 

—Erik Greb
Senior Associate Editor

Living in the stroke belt as an adolescent is significantly associated with a high risk of stroke, according to research published online ahead of print April 24 in Neurology. Researchers examined data for 24,544 stroke-free participants in the Reasons for Geographic and Racial Differences in Stroke study. Stroke belt exposure was calculated by combinations of stroke belt birthplace, current residence, and proportion of years in the stroke belt during discrete age categories. Risk of stroke was significantly associated with proportion of life in the stroke belt and with all other exposure periods except birth, ages 31 to 45, and current residence. After adjustment for risk factors, the risk of stroke remained significantly associated only with proportion of residence in the stroke belt during adolescence.

Increased levels of trimethylamine-N-oxide (TMAO), a proatherosclerotic metabolite, are associated with an increased risk of stroke, myocardial infarction, or death, according to research published in the April 25 New England Journal of Medicine. Investigators measured TMAO, choline, and betaine levels in patients who had eaten two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine before and after suppressing intestinal microbiota with antibiotics. They also examined the relationship between fasting plasma levels of TMAO and major adverse cardiovascular events during three years of follow-up. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event. An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors, as well as in lower-risk subgroups.

A single-nucleotide polymorphism (SNP) in the ABCA7 gene was significantly linked with an increased risk of Alzheimer’s disease among African Americans, according to research published in the April 10 JAMA. African Americans with this mutation have nearly double the risk of Alzheimer’s disease, but the SNP is not associated with the disease among Europeans. The effect size for the SNP in ABCA7 was comparable with that of the APOE ε4–determining SNP rs429358. Investigators examined data for 5,896 African Americans (1,968 with Alzheimer’s disease and 3,928 controls) who were 60 or older. Data were collected between 1989 and 2011 at multiple sites. The team assessed the association of Alzheimer’s disease with genotyped and imputed SNPs in case–control and in family-based data sets.

The FDA has approved the Precision Spectra Spinal Cord Stimulator (SCS) System, which is designed to provide improved pain relief to patients with chronic pain. The system, manufactured by Boston Scientific (Natick, Massachusetts), includes Illumina 3D software intended to improve physicians’ control of the stimulation field. It is based on a proprietary computer model that takes into account 3-D anatomical structures, including the conductivity of the spinal cord and surrounding tissue. The physician can select a desired location on the spinal cord and prompt the programming software to create a customized stimulation field to mask the patient’s pain. Previous SCS systems included 16 contacts, but the Precision Spectra system includes 32 contacts and is designed to offer more coverage of the spinal cord.

Framingham risk scores may be better than a dementia risk score for assessing individuals’ risk of cognitive decline and targeting modifiable risk factors, according to research published in the April 2 Neurology. Researchers examined data for participants in the Whitehall II longitudinal cohort study. Subjects’ mean age at baseline was 55.6. The investigators compared the Framingham general cardiovascular disease risk score and the Framingham stroke risk score with the Cardiovascular Risk Factors, Aging, and Dementia risk score. Patients underwent cognitive tests of reasoning, memory, verbal fluency, vocabulary, and global cognition three times over 10 years. Compared with the dementia risk score, cardiovascular and stroke risk scores showed slightly stronger associations with 10-year cognitive decline. The differences were statistically significant for semantic fluency and global cognitive scores.

Children born to women who used valproate during pregnancy may have a significantly increased risk of autism spectrum disorder and childhood autism, according to research published in the April 24 JAMA. Investigators used national registers to identify Danish children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders. The researchers analyzed the risks associated with all autism spectrum disorders, as well as childhood autism, and adjusted for potential confounders. The estimated absolute risk after 14 years of follow-up was 1.53% for autism spectrum disorder and 0.48% for childhood autism. The 508 children exposed to valproate had an absolute risk of 4.42% for autism spectrum disorder and an absolute risk of 2.50% for childhood autism. Results changed slightly after considering only the children born to women with epilepsy.

The antisense oligonucleotide ISIS 333611 is a safe treatment for amyotrophic lateral sclerosis (ALS), according to a trial published online ahead of print March 29 in Lancet Neurology. Investigators studied 32 patients with SOD1-positive ALS in a randomized, placebo-controlled, phase I trial. The researchers delivered the drug by intrathecal infusion using an external pump over 11.5 hours at increasing doses (0.15 mg, 0.50 mg, 1.50 mg, and 3.00 mg). Approximately 88% of patients in the placebo group had adverse events, compared with 83% in the active group. The most common events were post-lumbar puncture syndrome, back pain, and nausea. The investigators found no dose-limiting toxic effects or safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611.

 

Thalamic atrophy in patients with clinically isolated syndrome (CIS) is associated with the development of clinically definite multiple sclerosis (MS), according to a study published online ahead of print April 23 in Radiology. Using MRI, researchers assessed 216 patients with CIS at baseline, six months, one year, and two years. MRI measures of progression included new and enlarged T2 lesions and changes in whole-brain, tissue-specific global, and regional gray matter volumes. In mixed-effect model analysis, the lateral ventricle volume, accumulation of new total T2 and new enlarging T2 lesions increase, and thalamic and whole-brain volume decrease were associated with development of clinically definite MS. In multivariate regression analysis, decrease in thalamic volumes and increase in lateral ventricle volumes were associated with the development of clinically definite MS.

Functional MRI (fMRI) can identify pain caused by heat in healthy persons, according to research published in the April 11 New England Journal of Medicine. In four studies of 114 participants, investigators developed an fMRI-based measure that predicts pain intensity, tested its sensitivity and specificity to pain versus warmth, assessed its specificity relative to social pain, and assessed the responsiveness of the measure to the analgesic remifentanil. The neurologic signature distinguished painful heat from nonpainful warmth, pain anticipation, and pain recall with sensitivity and specificity of 94% or more. The signature discriminated between painful heat and nonpainful warmth with 93% sensitivity and specificity. It also distinguished between physical pain and social pain with 85% sensitivity and 73% specificity. The strength of the signature response was substantially reduced after remifentanil administration.

Family history of late-onset Alzheimer’s disease is associated with an increased prevalence of an abnormal cerebral beta-amyloid and tau protein phenotype in patients with mild cognitive impairment (MCI), according to a study published on April 17 in PLOS One. Investigators studied 257 participants (ages 55 to 89) in the Alzheimer’s Disease Neuroimaging Initiative. Subjects were categorized as cognitively normal, having MCI, or having Alzheimer’s disease. Among patients with MCI, CSF Ab42 was lower, t-tau was higher, and t-tau–Ab42 ratio was higher in patients with a family history of Alzheimer’s disease than in patients without. A significant residual effect of family history on pathologic markers in MCI remained after adjusting for APOE e4. The effect of family history was not significant in patients with Alzheimer’s disease.

Most potential migraine triggers are so variable that it may not be possible to identify them without formal experimentation, according to a study published in the April issue of Headache. Investigators examined the similarity of day-to-day weather conditions over four years, as well as the similarity of ovarian hormones and perceived stress over a median of 89 days in nine patients with headache and regular menstrual cycles. A threshold of 90% similarity using Gower’s index identified similar days for comparison. The day-to-day variability in the three headache triggers was substantial enough that finding two naturally similar days for which to contrast the effect of a fourth trigger (eg, drinking wine) occurred infrequently. Fluctuations in weather patterns resulted in a median of 2.3 similar days each year.

Elevated low-density lipoprotein (LDL) cholesterol and altered cholesterol homeostasis may promote neurodegeneration, atherosclerosis, and Alzheimer’s disease by disrupting chromosome segregation, according to research published on April 12 in PLOS One. In a study of mice, investigators observed that high dietary cholesterol induced aneuploidy. In a separate study, the accumulation of intracellular cholesterol was associated with the accumulation of aneuploid fibroblasts, neurons, and glia in patients with Niemann-Pick C1. The researchers also observed that oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induced chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors. LDL-induced aneuploidy required the LDL receptor, but not Ab. Cholesterol treatment disrupted the structure of the mitotic spindle, providing a cell biologic mechanism for its aneugenic activity, and ethanol or calcium chelation attenuated lipoprotein-induced chromosome mis-segregation.

The incidence of dementia in central Stockholm may have decreased from the late 1980s to the early 2000s, according to research published online ahead of print April 17 in Neurology. Investigators analyzed data from two cross-sectional surveys of people ages 75 or older. One study was conducted from 1987 to 1989 and included 1,700 participants; the other was conducted from 2001 to 2004 and included 1,575 subjects. The team inferred the incidence of dementia according to its relationship with prevalence and survival. The adjusted odds ratio of dementia in the later study versus the earlier study was 1.17. The multiadjusted hazard ratio of death in the later study versus the earlier study was 0.71 in subjects with dementia, 0.68 in those without dementia, and 0.66 in all participants.

 

—Erik Greb
Senior Associate Editor