Neurodevelopmental Disorders

VANCOUVER—Among newborns at risk of neurologic dysfunction, measures of neonatal sleep help predict 18-month neurodevelopmental outcomes, according to research presented at the 45th Annual Meeting of the Child Neurology Society.

Studies suggest that abnormal sleep has neurocognitive consequences for older infants and children and that polysomnogram data are associated with brain function in newborns who require neonatal intensive care. “Although sleep is a highly sophisticated brain function, it is not typically included in the newborn clinical neurological assessment,” said Renée A. Shellhaas, MD, MS, Assistant Professor of Pediatrics and Communicable Diseases at the University of Michigan in Ann Arbor, and colleagues.

To evaluate how polysomnography measures may add to standard predictors of neurodevelopmental outcome for newborns who require intensive care and are at risk for neurologic dysfunction, Dr. Shellhaas and colleagues conducted a longitudinal study of 29 newborns. Patients had a gestational age of 35 weeks or more, were cared for in a neonatal intensive care unit, and were clinically determined to be at risk of seizures. Researchers excluded patients with congenital anomalies or syndromes known to affect neurodevelopmental outcome or predispose patients to sleep-disordered breathing. They also excluded patients who had severely abnormal EEG without sleep–wake cycling.

Once a newborn was medically stable, researchers conducted a 12-hour attended, bedside polysomnogram. Polysomnograms were scored by a polysomnography technologist and reviewed by a sleep-medicine physician. Researchers calculated the proportion of each sleep–wake stage, entropy of the sequence of sleep–wake state transitions, and power spectra of the EEG portion of the polysomnogram.

Researchers evaluated neurodevelopmental outcome at 18 months to 22 months using the third edition of the Bayley Scales of Infant Development (BSID). They assessed associations between polysomnogram results and neurodevelopmental outcomes using regression techniques that de-emphasized outliers. Patients’ mean gestational age was 39.6 weeks. Seventeen of the 29 patients were male. Mean birth weight was 3.42 kg, and median five-minute Apgar score was 8.

In univariate analysis, increased time in quiet sleep predicted lower 18-month cognitive, language, and motor BSID scores. Higher entropy of sleep–wake transitions predicted lower motor scores. Increased low-frequency EEG power during quiet sleep predicted higher motor and language BSID scores. Gestational age and illness severity were not predictive of BSID results. A more abnormal neonatal neurologic exam score (ie, Thompson score) predicted lower cognitive and motor BSID scores.

In analyses adjusted for Thompson score, higher EEG power during neonatal quiet sleep was associated with better 18-month motor and language scores. In addition, increased time in neonatal quiet sleep was associated with lower 18-month cognitive and motor scores. “Notably, Thompson score was not an independent predictor of outcome when the sleep data were included in the bivariate models,” Dr. Shellhaas and colleagues said.

“Our results suggest that inefficient neonatal quiet sleep—more time in quiet sleep and lower delta frequency power during that stage—predicts lower 18-month neurodevelopmental outcome scores,” the researchers concluded. “Importantly, these novel measures of brain functional integrity were robust predictors even after adjusting for the neonatal neurologic examination score.”

—Jake Remaly

Suggested Reading

Shellhaas RA, Burns JW, Barks JD, Chervin RD. Quantitative sleep stage analyses as a window to neonatal neurologic function. Neurology. 2014;82(5):390-395.

Shellhaas RA, Burns JW, Wiggins SA, et al. Sleep-wake cycling and cerebral oxygen metabolism among critically ill neonates. J Child Neurol. 2014;29(4):530-533.

VANCOUVER—Among newborns at risk of neurologic dysfunction, measures of neonatal sleep help predict 18-month neurodevelopmental outcomes, according to research presented at the 45th Annual Meeting of the Child Neurology Society.

Studies suggest that abnormal sleep has neurocognitive consequences for older infants and children and that polysomnogram data are associated with brain function in newborns who require neonatal intensive care. “Although sleep is a highly sophisticated brain function, it is not typically included in the newborn clinical neurological assessment,” said Renée A. Shellhaas, MD, MS, Assistant Professor of Pediatrics and Communicable Diseases at the University of Michigan in Ann Arbor, and colleagues.

To evaluate how polysomnography measures may add to standard predictors of neurodevelopmental outcome for newborns who require intensive care and are at risk for neurologic dysfunction, Dr. Shellhaas and colleagues conducted a longitudinal study of 29 newborns. Patients had a gestational age of 35 weeks or more, were cared for in a neonatal intensive care unit, and were clinically determined to be at risk of seizures. Researchers excluded patients with congenital anomalies or syndromes known to affect neurodevelopmental outcome or predispose patients to sleep-disordered breathing. They also excluded patients who had severely abnormal EEG without sleep–wake cycling.

Once a newborn was medically stable, researchers conducted a 12-hour attended, bedside polysomnogram. Polysomnograms were scored by a polysomnography technologist and reviewed by a sleep-medicine physician. Researchers calculated the proportion of each sleep–wake stage, entropy of the sequence of sleep–wake state transitions, and power spectra of the EEG portion of the polysomnogram.

Researchers evaluated neurodevelopmental outcome at 18 months to 22 months using the third edition of the Bayley Scales of Infant Development (BSID). They assessed associations between polysomnogram results and neurodevelopmental outcomes using regression techniques that de-emphasized outliers. Patients’ mean gestational age was 39.6 weeks. Seventeen of the 29 patients were male. Mean birth weight was 3.42 kg, and median five-minute Apgar score was 8.

In univariate analysis, increased time in quiet sleep predicted lower 18-month cognitive, language, and motor BSID scores. Higher entropy of sleep–wake transitions predicted lower motor scores. Increased low-frequency EEG power during quiet sleep predicted higher motor and language BSID scores. Gestational age and illness severity were not predictive of BSID results. A more abnormal neonatal neurologic exam score (ie, Thompson score) predicted lower cognitive and motor BSID scores.

In analyses adjusted for Thompson score, higher EEG power during neonatal quiet sleep was associated with better 18-month motor and language scores. In addition, increased time in neonatal quiet sleep was associated with lower 18-month cognitive and motor scores. “Notably, Thompson score was not an independent predictor of outcome when the sleep data were included in the bivariate models,” Dr. Shellhaas and colleagues said.

“Our results suggest that inefficient neonatal quiet sleep—more time in quiet sleep and lower delta frequency power during that stage—predicts lower 18-month neurodevelopmental outcome scores,” the researchers concluded. “Importantly, these novel measures of brain functional integrity were robust predictors even after adjusting for the neonatal neurologic examination score.”

—Jake Remaly

Suggested Reading

Shellhaas RA, Burns JW, Barks JD, Chervin RD. Quantitative sleep stage analyses as a window to neonatal neurologic function. Neurology. 2014;82(5):390-395.

Shellhaas RA, Burns JW, Wiggins SA, et al. Sleep-wake cycling and cerebral oxygen metabolism among critically ill neonates. J Child Neurol. 2014;29(4):530-533.

VANCOUVER—Among newborns at risk of neurologic dysfunction, measures of neonatal sleep help predict 18-month neurodevelopmental outcomes, according to research presented at the 45th Annual Meeting of the Child Neurology Society.

Studies suggest that abnormal sleep has neurocognitive consequences for older infants and children and that polysomnogram data are associated with brain function in newborns who require neonatal intensive care. “Although sleep is a highly sophisticated brain function, it is not typically included in the newborn clinical neurological assessment,” said Renée A. Shellhaas, MD, MS, Assistant Professor of Pediatrics and Communicable Diseases at the University of Michigan in Ann Arbor, and colleagues.

To evaluate how polysomnography measures may add to standard predictors of neurodevelopmental outcome for newborns who require intensive care and are at risk for neurologic dysfunction, Dr. Shellhaas and colleagues conducted a longitudinal study of 29 newborns. Patients had a gestational age of 35 weeks or more, were cared for in a neonatal intensive care unit, and were clinically determined to be at risk of seizures. Researchers excluded patients with congenital anomalies or syndromes known to affect neurodevelopmental outcome or predispose patients to sleep-disordered breathing. They also excluded patients who had severely abnormal EEG without sleep–wake cycling.

Once a newborn was medically stable, researchers conducted a 12-hour attended, bedside polysomnogram. Polysomnograms were scored by a polysomnography technologist and reviewed by a sleep-medicine physician. Researchers calculated the proportion of each sleep–wake stage, entropy of the sequence of sleep–wake state transitions, and power spectra of the EEG portion of the polysomnogram.

Researchers evaluated neurodevelopmental outcome at 18 months to 22 months using the third edition of the Bayley Scales of Infant Development (BSID). They assessed associations between polysomnogram results and neurodevelopmental outcomes using regression techniques that de-emphasized outliers. Patients’ mean gestational age was 39.6 weeks. Seventeen of the 29 patients were male. Mean birth weight was 3.42 kg, and median five-minute Apgar score was 8.

In univariate analysis, increased time in quiet sleep predicted lower 18-month cognitive, language, and motor BSID scores. Higher entropy of sleep–wake transitions predicted lower motor scores. Increased low-frequency EEG power during quiet sleep predicted higher motor and language BSID scores. Gestational age and illness severity were not predictive of BSID results. A more abnormal neonatal neurologic exam score (ie, Thompson score) predicted lower cognitive and motor BSID scores.

In analyses adjusted for Thompson score, higher EEG power during neonatal quiet sleep was associated with better 18-month motor and language scores. In addition, increased time in neonatal quiet sleep was associated with lower 18-month cognitive and motor scores. “Notably, Thompson score was not an independent predictor of outcome when the sleep data were included in the bivariate models,” Dr. Shellhaas and colleagues said.

“Our results suggest that inefficient neonatal quiet sleep—more time in quiet sleep and lower delta frequency power during that stage—predicts lower 18-month neurodevelopmental outcome scores,” the researchers concluded. “Importantly, these novel measures of brain functional integrity were robust predictors even after adjusting for the neonatal neurologic examination score.”

—Jake Remaly

Suggested Reading

Shellhaas RA, Burns JW, Barks JD, Chervin RD. Quantitative sleep stage analyses as a window to neonatal neurologic function. Neurology. 2014;82(5):390-395.

Shellhaas RA, Burns JW, Wiggins SA, et al. Sleep-wake cycling and cerebral oxygen metabolism among critically ill neonates. J Child Neurol. 2014;29(4):530-533.

A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.

“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.

Follow-Up of 11 Neonates

Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.

Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.

Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.

“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.

Formulating a Plan of Action

“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”

But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”

—Glenn S. Williams

Suggested Reading

Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.

“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.

Follow-Up of 11 Neonates

Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.

Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.

Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.

“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.

Formulating a Plan of Action

“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”

But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”

—Glenn S. Williams

Suggested Reading

Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

A report on 11 infants in Brazil suggests the term “congenital Zika syndrome” be used to describe the abnormalities associated with Zika virus infection because microcephaly is only one clinical sign of this congenital malformation disorder. The report was published online ahead of print October 3 in JAMA Neurology.

“To our knowledge,” the researchers wrote, “most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects.” To provide a fuller description, the researchers sought to characterize the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurologic damage associated with Zika infection.

Follow-Up of 11 Neonates

Amilcar Tanuri, MD, PhD, Professor of Genetics and Chief of the Laboratory of Molecular Virology at the Institute of Biology, Federal University of Rio de Janeiro, and coauthors observed 11 infants with congenital Zika infection from gestation to six months in the state of Paraíba, Brazil. Cases were referred between October 2015 and February 2016. Ten of 11 women included in the study presented with symptoms of Zika infection during the first half of pregnancy, and all 11 had laboratory evidence of infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by MRI. Histopathologic analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis.

Of the 11 infants, seven (63.6%) were female, and the median maternal age at delivery was 25. Three of the neonates died, giving a perinatal mortality rate of 27.3%. Zika virus was identified in amniotic fluid, placenta, cord blood, and neonatal tissues collected post mortem in the three babies who died within 48 hours of delivery.

Brain damage and neurologic impairments were identified in all patients, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence. Testing for other causes of microcephaly, such as genetic disorders and infections, was negative. The ZIKV virus genome was found in tissues of the mothers and their babies.

“Combined findings from clinical, laboratory, imaging, and pathologic examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported,” Dr. Tanuri and colleagues said.

Formulating a Plan of Action

“Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing,” said Raymond P. Roos, MD, Marjorie and Robert E. Straus Professor in Neurologic Science in the Department of Neurology at the University of Chicago, in an accompanying editorial. “We also have novel methods to control vectors and produce vaccines in an accelerated time frame.”

But many unanswered questions remain, said Dr. Roos. Among those questions is what neurologists can do about the Zika virus. “It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus-induced Guillain-Barré syndrome (GBS) and CNS disease. This [cooperation] would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiologic studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome.”

—Glenn S. Williams

Suggested Reading

Melo AS, Aguiar RS, Amorim MM, et al. Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

Roos RP. Zika virus-a public health emergency of international concern. JAMA Neurol. 2016 Oct 3 [Epub ahead of print].

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

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

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

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

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

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

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