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Conference News Roundup—American Heart Association
Does Cholesterol Testing Reduce Risk of Recurrent Stroke?
When a patient has a heart attack or stroke, it is critical for his or her clinician to perform a follow-up cholesterol test, according to a study conducted at the Intermountain Medical Center Heart Institute in Salt Lake City. This additional measure is significantly associated with reduced risk of having another serious cardiovascular episode.
Investigators found that patients who do not follow up with their doctor by getting a low-density lipoprotein (LDL) cholesterol test after a heart attack or stroke are significantly more likely to have a recurrence. They also found a significant and clinically meaningful difference in major adverse outcomes—including death, heart attack, stroke, and a vascular bypass or an angioplasty—based on whether or not a patient has a follow-up measurement of his or her LDL cholesterol.
“It is clear that anyone with a previous heart problem caused by clogged arteries should be taking a cholesterol-lowering medication,” said Kirk U. Knowlton, MD, Director of Cardiovascular Research at the Intermountain Medical Center Heart Institute.
The study of more than 60,000 patients with known heart disease, cerebrovascular disease, or peripheral artery disease, including patients with stroke and heart attack, showed that the major adverse clinical event rate was lower in patients who took cholesterol-lowering statins and in those who did not take them if their LDL was measured.
“The large difference is surprising. The risk of dying after three years with no LDL follow-up is 21% versus 5.9% for patients who have an LDL follow-up,” said Dr. Knowlton.
Researchers reviewed Intermountain Healthcare’s enterprise data warehouse to identify all adults who came to one of Intermountain’s 22 hospitals for the first time with a heart attack or stroke. These data included patients with coronary artery disease, cerebrovascular disease, and peripheral arterial disease admitted between January 1, 1999, and December 31, 2013.
Investigators observed patients who survived and were followed for three years or more or until their death. Patient demographics, history, prescribed medications, and whether LDL was measured was analyzed.
The study compared 62,070 patients in the database who met the study criteria. The mean age was 66, and 65% of patients were male. Of those who met the criteria, 69.3% had coronary artery disease, 18.6% had cerebrovascular disease, and 12.1% had peripheral arterial disease when they came to the hospital with their first heart attack or stroke.
Researchers found that the risk of a patient having a secondary event or dying decreased in patients who had a follow-up LDL test before a subsequent adverse outcome or before the end of their follow-up.
Coffee Is Associated With Lower Risk of Heart Failure and Stroke
Drinking coffee may be associated with a decreased risk of heart failure or stroke, according to researchers.
Investigators used machine learning to analyze data from the long-running Framingham Heart Study, which includes information about what people eat and their cardiovascular health. They found that every additional cup of coffee consumed per week was associated with a 7% decreased risk of heart failure and an 8% reduced risk of stroke, compared with non-coffee drinkers.
The researchers further investigated the machine learning results using traditional analysis in two studies with similar sets of data: the Cardiovascular Heart Study and the Atherosclerosis Risk In Communities Study. The association between drinking coffee and a decreased risk of heart failure and stroke was observed consistently in all three studies.
Another potential risk factor identified by machine-learning analysis was red meat consumption. The association between red meat consumption and heart failure or stroke was less clear, however. Eating red meat was associated with decreased risk of heart failure and stroke in the Framingham Heart Study, but validating the finding in comparable studies is more challenging due to differences in the definitions of red meat between studies, said the researchers. Further investigation to better determine how red meat consumption affects risk for heart failure and stroke is ongoing.
The researchers also built a predictive model using known risk factors from the Framingham Risk Score such as blood pressure, age, and other patient characteristics associated with cardiovascular disease. “By including coffee in the model, the prediction accuracy increased by 4%. Machine learning may be a useful addition to the way we look at data and may help us to find new ways to lower the risk of heart failure and strokes,” said David Kao, MD, Assistant Professor of Medicine in the Division of Cardiology at the University of Colorado School of Medicine in Aurora.
Statins May Improve Stroke Outcome
Patients with a prior history of heart attack or stroke have better outcomes when cholesterol-lowering medications are used after they are discharged from the hospital, according to researchers.
Prior surveys in hospitals found that statins are not being used consistently in patients who have been admitted to the hospital following a heart attack or stroke. Researchers also found that when the medication is prescribed, dosing is likely not as high as it should be to provide optimal benefits.
Researchers examined more than 62,000 records of patients from the Intermountain Healthcare system between 1999 and 2013 who survived an initial atherosclerotic cardiovascular disease event, such as a heart attack or stroke. They were then followed for three years or until death to identify the effectiveness of statin use prescribed at the time of their discharge.
“Patients who were prescribed a statin medication following an initial heart attack or stroke reduced their risk of a future adverse event such as a future heart attack, stroke, revascularization, or death by almost 25%—the rate dropped from 34% to 26%,” said Jeffrey L. Anderson, MD, a cardiovascular researcher at the Intermountain Medical Center Heart Institute. “The patients who were discharged on what is considered a high-intensity dose of a statin saw a 21% reduction in their risk,” compared with those discharged on a low-intensity statin dose.”
Investigators found that 30% of patients in the study who were discharged from the hospital following a heart attack or stroke were not prescribed a statin. This factor led to worse outcomes for those patients.
Researchers also found that only 13% of patients were given a high-intensity dose of statins, but noted that patients on those higher doses experienced fewer heart attacks or strokes. For patients younger than age 76, a high-intensity statin is indicated, according to American Heart Association guidelines. Only 17.7% of these patients were discharged on a high-intensity dose, however.
Does Cholesterol Testing Reduce Risk of Recurrent Stroke?
When a patient has a heart attack or stroke, it is critical for his or her clinician to perform a follow-up cholesterol test, according to a study conducted at the Intermountain Medical Center Heart Institute in Salt Lake City. This additional measure is significantly associated with reduced risk of having another serious cardiovascular episode.
Investigators found that patients who do not follow up with their doctor by getting a low-density lipoprotein (LDL) cholesterol test after a heart attack or stroke are significantly more likely to have a recurrence. They also found a significant and clinically meaningful difference in major adverse outcomes—including death, heart attack, stroke, and a vascular bypass or an angioplasty—based on whether or not a patient has a follow-up measurement of his or her LDL cholesterol.
“It is clear that anyone with a previous heart problem caused by clogged arteries should be taking a cholesterol-lowering medication,” said Kirk U. Knowlton, MD, Director of Cardiovascular Research at the Intermountain Medical Center Heart Institute.
The study of more than 60,000 patients with known heart disease, cerebrovascular disease, or peripheral artery disease, including patients with stroke and heart attack, showed that the major adverse clinical event rate was lower in patients who took cholesterol-lowering statins and in those who did not take them if their LDL was measured.
“The large difference is surprising. The risk of dying after three years with no LDL follow-up is 21% versus 5.9% for patients who have an LDL follow-up,” said Dr. Knowlton.
Researchers reviewed Intermountain Healthcare’s enterprise data warehouse to identify all adults who came to one of Intermountain’s 22 hospitals for the first time with a heart attack or stroke. These data included patients with coronary artery disease, cerebrovascular disease, and peripheral arterial disease admitted between January 1, 1999, and December 31, 2013.
Investigators observed patients who survived and were followed for three years or more or until their death. Patient demographics, history, prescribed medications, and whether LDL was measured was analyzed.
The study compared 62,070 patients in the database who met the study criteria. The mean age was 66, and 65% of patients were male. Of those who met the criteria, 69.3% had coronary artery disease, 18.6% had cerebrovascular disease, and 12.1% had peripheral arterial disease when they came to the hospital with their first heart attack or stroke.
Researchers found that the risk of a patient having a secondary event or dying decreased in patients who had a follow-up LDL test before a subsequent adverse outcome or before the end of their follow-up.
Coffee Is Associated With Lower Risk of Heart Failure and Stroke
Drinking coffee may be associated with a decreased risk of heart failure or stroke, according to researchers.
Investigators used machine learning to analyze data from the long-running Framingham Heart Study, which includes information about what people eat and their cardiovascular health. They found that every additional cup of coffee consumed per week was associated with a 7% decreased risk of heart failure and an 8% reduced risk of stroke, compared with non-coffee drinkers.
The researchers further investigated the machine learning results using traditional analysis in two studies with similar sets of data: the Cardiovascular Heart Study and the Atherosclerosis Risk In Communities Study. The association between drinking coffee and a decreased risk of heart failure and stroke was observed consistently in all three studies.
Another potential risk factor identified by machine-learning analysis was red meat consumption. The association between red meat consumption and heart failure or stroke was less clear, however. Eating red meat was associated with decreased risk of heart failure and stroke in the Framingham Heart Study, but validating the finding in comparable studies is more challenging due to differences in the definitions of red meat between studies, said the researchers. Further investigation to better determine how red meat consumption affects risk for heart failure and stroke is ongoing.
The researchers also built a predictive model using known risk factors from the Framingham Risk Score such as blood pressure, age, and other patient characteristics associated with cardiovascular disease. “By including coffee in the model, the prediction accuracy increased by 4%. Machine learning may be a useful addition to the way we look at data and may help us to find new ways to lower the risk of heart failure and strokes,” said David Kao, MD, Assistant Professor of Medicine in the Division of Cardiology at the University of Colorado School of Medicine in Aurora.
Statins May Improve Stroke Outcome
Patients with a prior history of heart attack or stroke have better outcomes when cholesterol-lowering medications are used after they are discharged from the hospital, according to researchers.
Prior surveys in hospitals found that statins are not being used consistently in patients who have been admitted to the hospital following a heart attack or stroke. Researchers also found that when the medication is prescribed, dosing is likely not as high as it should be to provide optimal benefits.
Researchers examined more than 62,000 records of patients from the Intermountain Healthcare system between 1999 and 2013 who survived an initial atherosclerotic cardiovascular disease event, such as a heart attack or stroke. They were then followed for three years or until death to identify the effectiveness of statin use prescribed at the time of their discharge.
“Patients who were prescribed a statin medication following an initial heart attack or stroke reduced their risk of a future adverse event such as a future heart attack, stroke, revascularization, or death by almost 25%—the rate dropped from 34% to 26%,” said Jeffrey L. Anderson, MD, a cardiovascular researcher at the Intermountain Medical Center Heart Institute. “The patients who were discharged on what is considered a high-intensity dose of a statin saw a 21% reduction in their risk,” compared with those discharged on a low-intensity statin dose.”
Investigators found that 30% of patients in the study who were discharged from the hospital following a heart attack or stroke were not prescribed a statin. This factor led to worse outcomes for those patients.
Researchers also found that only 13% of patients were given a high-intensity dose of statins, but noted that patients on those higher doses experienced fewer heart attacks or strokes. For patients younger than age 76, a high-intensity statin is indicated, according to American Heart Association guidelines. Only 17.7% of these patients were discharged on a high-intensity dose, however.
Does Cholesterol Testing Reduce Risk of Recurrent Stroke?
When a patient has a heart attack or stroke, it is critical for his or her clinician to perform a follow-up cholesterol test, according to a study conducted at the Intermountain Medical Center Heart Institute in Salt Lake City. This additional measure is significantly associated with reduced risk of having another serious cardiovascular episode.
Investigators found that patients who do not follow up with their doctor by getting a low-density lipoprotein (LDL) cholesterol test after a heart attack or stroke are significantly more likely to have a recurrence. They also found a significant and clinically meaningful difference in major adverse outcomes—including death, heart attack, stroke, and a vascular bypass or an angioplasty—based on whether or not a patient has a follow-up measurement of his or her LDL cholesterol.
“It is clear that anyone with a previous heart problem caused by clogged arteries should be taking a cholesterol-lowering medication,” said Kirk U. Knowlton, MD, Director of Cardiovascular Research at the Intermountain Medical Center Heart Institute.
The study of more than 60,000 patients with known heart disease, cerebrovascular disease, or peripheral artery disease, including patients with stroke and heart attack, showed that the major adverse clinical event rate was lower in patients who took cholesterol-lowering statins and in those who did not take them if their LDL was measured.
“The large difference is surprising. The risk of dying after three years with no LDL follow-up is 21% versus 5.9% for patients who have an LDL follow-up,” said Dr. Knowlton.
Researchers reviewed Intermountain Healthcare’s enterprise data warehouse to identify all adults who came to one of Intermountain’s 22 hospitals for the first time with a heart attack or stroke. These data included patients with coronary artery disease, cerebrovascular disease, and peripheral arterial disease admitted between January 1, 1999, and December 31, 2013.
Investigators observed patients who survived and were followed for three years or more or until their death. Patient demographics, history, prescribed medications, and whether LDL was measured was analyzed.
The study compared 62,070 patients in the database who met the study criteria. The mean age was 66, and 65% of patients were male. Of those who met the criteria, 69.3% had coronary artery disease, 18.6% had cerebrovascular disease, and 12.1% had peripheral arterial disease when they came to the hospital with their first heart attack or stroke.
Researchers found that the risk of a patient having a secondary event or dying decreased in patients who had a follow-up LDL test before a subsequent adverse outcome or before the end of their follow-up.
Coffee Is Associated With Lower Risk of Heart Failure and Stroke
Drinking coffee may be associated with a decreased risk of heart failure or stroke, according to researchers.
Investigators used machine learning to analyze data from the long-running Framingham Heart Study, which includes information about what people eat and their cardiovascular health. They found that every additional cup of coffee consumed per week was associated with a 7% decreased risk of heart failure and an 8% reduced risk of stroke, compared with non-coffee drinkers.
The researchers further investigated the machine learning results using traditional analysis in two studies with similar sets of data: the Cardiovascular Heart Study and the Atherosclerosis Risk In Communities Study. The association between drinking coffee and a decreased risk of heart failure and stroke was observed consistently in all three studies.
Another potential risk factor identified by machine-learning analysis was red meat consumption. The association between red meat consumption and heart failure or stroke was less clear, however. Eating red meat was associated with decreased risk of heart failure and stroke in the Framingham Heart Study, but validating the finding in comparable studies is more challenging due to differences in the definitions of red meat between studies, said the researchers. Further investigation to better determine how red meat consumption affects risk for heart failure and stroke is ongoing.
The researchers also built a predictive model using known risk factors from the Framingham Risk Score such as blood pressure, age, and other patient characteristics associated with cardiovascular disease. “By including coffee in the model, the prediction accuracy increased by 4%. Machine learning may be a useful addition to the way we look at data and may help us to find new ways to lower the risk of heart failure and strokes,” said David Kao, MD, Assistant Professor of Medicine in the Division of Cardiology at the University of Colorado School of Medicine in Aurora.
Statins May Improve Stroke Outcome
Patients with a prior history of heart attack or stroke have better outcomes when cholesterol-lowering medications are used after they are discharged from the hospital, according to researchers.
Prior surveys in hospitals found that statins are not being used consistently in patients who have been admitted to the hospital following a heart attack or stroke. Researchers also found that when the medication is prescribed, dosing is likely not as high as it should be to provide optimal benefits.
Researchers examined more than 62,000 records of patients from the Intermountain Healthcare system between 1999 and 2013 who survived an initial atherosclerotic cardiovascular disease event, such as a heart attack or stroke. They were then followed for three years or until death to identify the effectiveness of statin use prescribed at the time of their discharge.
“Patients who were prescribed a statin medication following an initial heart attack or stroke reduced their risk of a future adverse event such as a future heart attack, stroke, revascularization, or death by almost 25%—the rate dropped from 34% to 26%,” said Jeffrey L. Anderson, MD, a cardiovascular researcher at the Intermountain Medical Center Heart Institute. “The patients who were discharged on what is considered a high-intensity dose of a statin saw a 21% reduction in their risk,” compared with those discharged on a low-intensity statin dose.”
Investigators found that 30% of patients in the study who were discharged from the hospital following a heart attack or stroke were not prescribed a statin. This factor led to worse outcomes for those patients.
Researchers also found that only 13% of patients were given a high-intensity dose of statins, but noted that patients on those higher doses experienced fewer heart attacks or strokes. For patients younger than age 76, a high-intensity statin is indicated, according to American Heart Association guidelines. Only 17.7% of these patients were discharged on a high-intensity dose, however.
CDC Updates Guidance on Infants With Possible Zika Infection
Infants with possible prenatal exposure to Zika who test positive for the virus should receive an in-depth ophthalmologic exam, intensified hearing testing, and a thorough neurologic evaluation with brain imaging within one month of birth, according to new interim guidance from the Centers for Disease Control and Prevention (CDC).
The new clinical management guidelines, published in the October 20 issue of Morbidity and Mortality Weekly Report, supersede the CDC guidance issued in August 2016. The update was the product of a forum on the diagnosis, evaluation, and management of Zika in infants that the centers convened with the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists. Practicing clinicians and federal agency representatives reviewed the evolving body of knowledge on how best to care for these infants. Since Zika emerged as a public health concern, clinicians have reported postnatal onset of some symptoms, including eye abnormalities, incident microcephaly in infants with a normal head circumference at birth, EEG abnormalities, and diaphragmatic paralysis.
Infants With Clinical Findings Consistent With Zika Syndrome
Infants with clinical findings consistent with congenital Zika syndrome who are born to mothers with possible Zika virus exposure in pregnancy should be tested for Zika virus with serum and urine tests. If those tests are negative, and there is no other apparent cause of the symptoms, they should have a CSF sample tested for Zika RNA and IgM Zika antibodies.
By one month, these infants should undergo a head ultrasound and a detailed ophthalmologic exam. The eye exam should pick up any anomalies of the anterior and posterior eye, including microphthalmia, coloboma, intraocular calcifications, optic nerve hypoplasia and atrophy, and macular scarring with focal pigmentary retinal mottling.
By one month, these infants also should undergo auditory brainstem response (ABR) audiometry, especially if the initial newborn hearing screen was done by otoacoustic emissions alone. Zika syndrome can include sensorineural hearing loss, although late-onset hearing loss has not been seen. Therefore, the follow-up ABR previously recommended at four to six months is no longer deemed necessary.
A comprehensive neurologic exam also is recommended. Seizures are sometimes part of Zika syndrome, but infants can also have subclinical EEG abnormalities. Advanced neuroimaging can identify obvious and subtle brain abnormalities, such as cortical thinning, corpus callosum abnormalities, calcifications at the junction of white and gray matter, and ventricular enlargement.
As infants grow, clinicians should be alert for signs of increased intracranial pressure that could signal postnatal hydrocephalus. Diaphragmatic paralysis also has been seen; it manifests as respiratory distress. Dysphagia that interferes with feeding can develop as well.
“The follow-up care of [these infants] requires a multidisciplinary team and an established medical home to facilitate the coordination of care and ensure that abnormal findings are addressed,” said Dr. Adebanjo and colleagues.
Asymptomatic Infants of Mothers With Possible Infection
Infants without clinical findings born to mothers with laboratory evidence of possible Zika virus infection during pregnancy should have the same early head ultrasound, hearing, and eye exams as those with clinical findings. All of these infants also should be tested for Zika virus just as those with clinical findings should be.
If tests are positive, these infants should have all the investigations and follow-up recommended for babies with clinical findings. If laboratory testing is negative, and clinical findings are normal, Zika infection is highly unlikely, and the infants can receive routine care. Clinicians and parents should be on the lookout, however, for new symptoms that might suggest postnatal Zika syndrome.
Asymptomatic Infants Whose Mothers Had Unconfirmed Zika Exposure
Infants without clinical findings consistent with congenital Zika syndrome born to mothers with possible Zika virus exposure in pregnancy, but without laboratory evidence of possible Zika virus infection during pregnancy, constitute a large group. Some women, for example, are never tested during pregnancy, and others have false negative test results. “Because the latter issues are not easily discerned, all mothers with possible exposure to Zika virus during pregnancy who do not have laboratory evidence of possible Zika virus infection, including those who tested negative with currently available technology, should be considered in this group,” said Dr. Adebanjo and colleagues.
The CDC do not recommend further Zika evaluation for these infants unless additional testing confirms maternal infection. For older infants, parents and clinicians should decide together whether further evaluations would be helpful. “If findings consistent with congenital Zika syndrome are identified at any time, referrals to the appropriate specialists should be made, and subsequent evaluation should follow recommendations for infants with clinical findings consistent with congenital Zika syndrome,” said the authors.
The CDC also reiterated their special recommendations for infants who had a prenatal diagnosis of Zika infection. For now, these recommendations remain unchanged, although “as more data become available, understanding of the diagnostic role of prenatal ultrasound and amniocentesis … will improve, and guidance will be updated.”
The optimal timing for a Zika diagnostic ultrasound is uncertain. The CDC recommend that serial ultrasounds be performed every three to four weeks for women with laboratory-confirmed prenatal Zika exposure. Women with possible exposure need only routine ultrasound screenings.
While Zika RNA has been identified in amniotic fluid, there is no consensus on the value of amniocentesis as a prenatal diagnostic tool. Investigations of serial amniocentesis suggest that viral shedding into the amniotic fluid might be transient. If amniocentesis is performed for other reasons, Zika nucleic acid testing can be incorporated.
A shared decision-making process about screening is key, said Dr. Adebanjo and colleagues. “For example, serial ultrasound examinations might be inconvenient, unpleasant, and expensive, and might prompt unnecessary interventions; amniocentesis carries additional known risks such as fetal loss. These potential harms of prenatal screening for congenital Zika syndrome might outweigh the clinical benefits for some patients; therefore, these decisions should be individualized.”
—Michele G. Sullivan
Suggested Reading
Adebanjo T, Godfred-Cato S, Viens L, et al. Update: Interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection - United States, October 2017. MMWR Morb Mortal Wkly Rep. 2017;66(41):1089-1099.
Infants with possible prenatal exposure to Zika who test positive for the virus should receive an in-depth ophthalmologic exam, intensified hearing testing, and a thorough neurologic evaluation with brain imaging within one month of birth, according to new interim guidance from the Centers for Disease Control and Prevention (CDC).
The new clinical management guidelines, published in the October 20 issue of Morbidity and Mortality Weekly Report, supersede the CDC guidance issued in August 2016. The update was the product of a forum on the diagnosis, evaluation, and management of Zika in infants that the centers convened with the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists. Practicing clinicians and federal agency representatives reviewed the evolving body of knowledge on how best to care for these infants. Since Zika emerged as a public health concern, clinicians have reported postnatal onset of some symptoms, including eye abnormalities, incident microcephaly in infants with a normal head circumference at birth, EEG abnormalities, and diaphragmatic paralysis.
Infants With Clinical Findings Consistent With Zika Syndrome
Infants with clinical findings consistent with congenital Zika syndrome who are born to mothers with possible Zika virus exposure in pregnancy should be tested for Zika virus with serum and urine tests. If those tests are negative, and there is no other apparent cause of the symptoms, they should have a CSF sample tested for Zika RNA and IgM Zika antibodies.
By one month, these infants should undergo a head ultrasound and a detailed ophthalmologic exam. The eye exam should pick up any anomalies of the anterior and posterior eye, including microphthalmia, coloboma, intraocular calcifications, optic nerve hypoplasia and atrophy, and macular scarring with focal pigmentary retinal mottling.
By one month, these infants also should undergo auditory brainstem response (ABR) audiometry, especially if the initial newborn hearing screen was done by otoacoustic emissions alone. Zika syndrome can include sensorineural hearing loss, although late-onset hearing loss has not been seen. Therefore, the follow-up ABR previously recommended at four to six months is no longer deemed necessary.
A comprehensive neurologic exam also is recommended. Seizures are sometimes part of Zika syndrome, but infants can also have subclinical EEG abnormalities. Advanced neuroimaging can identify obvious and subtle brain abnormalities, such as cortical thinning, corpus callosum abnormalities, calcifications at the junction of white and gray matter, and ventricular enlargement.
As infants grow, clinicians should be alert for signs of increased intracranial pressure that could signal postnatal hydrocephalus. Diaphragmatic paralysis also has been seen; it manifests as respiratory distress. Dysphagia that interferes with feeding can develop as well.
“The follow-up care of [these infants] requires a multidisciplinary team and an established medical home to facilitate the coordination of care and ensure that abnormal findings are addressed,” said Dr. Adebanjo and colleagues.
Asymptomatic Infants of Mothers With Possible Infection
Infants without clinical findings born to mothers with laboratory evidence of possible Zika virus infection during pregnancy should have the same early head ultrasound, hearing, and eye exams as those with clinical findings. All of these infants also should be tested for Zika virus just as those with clinical findings should be.
If tests are positive, these infants should have all the investigations and follow-up recommended for babies with clinical findings. If laboratory testing is negative, and clinical findings are normal, Zika infection is highly unlikely, and the infants can receive routine care. Clinicians and parents should be on the lookout, however, for new symptoms that might suggest postnatal Zika syndrome.
Asymptomatic Infants Whose Mothers Had Unconfirmed Zika Exposure
Infants without clinical findings consistent with congenital Zika syndrome born to mothers with possible Zika virus exposure in pregnancy, but without laboratory evidence of possible Zika virus infection during pregnancy, constitute a large group. Some women, for example, are never tested during pregnancy, and others have false negative test results. “Because the latter issues are not easily discerned, all mothers with possible exposure to Zika virus during pregnancy who do not have laboratory evidence of possible Zika virus infection, including those who tested negative with currently available technology, should be considered in this group,” said Dr. Adebanjo and colleagues.
The CDC do not recommend further Zika evaluation for these infants unless additional testing confirms maternal infection. For older infants, parents and clinicians should decide together whether further evaluations would be helpful. “If findings consistent with congenital Zika syndrome are identified at any time, referrals to the appropriate specialists should be made, and subsequent evaluation should follow recommendations for infants with clinical findings consistent with congenital Zika syndrome,” said the authors.
The CDC also reiterated their special recommendations for infants who had a prenatal diagnosis of Zika infection. For now, these recommendations remain unchanged, although “as more data become available, understanding of the diagnostic role of prenatal ultrasound and amniocentesis … will improve, and guidance will be updated.”
The optimal timing for a Zika diagnostic ultrasound is uncertain. The CDC recommend that serial ultrasounds be performed every three to four weeks for women with laboratory-confirmed prenatal Zika exposure. Women with possible exposure need only routine ultrasound screenings.
While Zika RNA has been identified in amniotic fluid, there is no consensus on the value of amniocentesis as a prenatal diagnostic tool. Investigations of serial amniocentesis suggest that viral shedding into the amniotic fluid might be transient. If amniocentesis is performed for other reasons, Zika nucleic acid testing can be incorporated.
A shared decision-making process about screening is key, said Dr. Adebanjo and colleagues. “For example, serial ultrasound examinations might be inconvenient, unpleasant, and expensive, and might prompt unnecessary interventions; amniocentesis carries additional known risks such as fetal loss. These potential harms of prenatal screening for congenital Zika syndrome might outweigh the clinical benefits for some patients; therefore, these decisions should be individualized.”
—Michele G. Sullivan
Suggested Reading
Adebanjo T, Godfred-Cato S, Viens L, et al. Update: Interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection - United States, October 2017. MMWR Morb Mortal Wkly Rep. 2017;66(41):1089-1099.
Infants with possible prenatal exposure to Zika who test positive for the virus should receive an in-depth ophthalmologic exam, intensified hearing testing, and a thorough neurologic evaluation with brain imaging within one month of birth, according to new interim guidance from the Centers for Disease Control and Prevention (CDC).
The new clinical management guidelines, published in the October 20 issue of Morbidity and Mortality Weekly Report, supersede the CDC guidance issued in August 2016. The update was the product of a forum on the diagnosis, evaluation, and management of Zika in infants that the centers convened with the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists. Practicing clinicians and federal agency representatives reviewed the evolving body of knowledge on how best to care for these infants. Since Zika emerged as a public health concern, clinicians have reported postnatal onset of some symptoms, including eye abnormalities, incident microcephaly in infants with a normal head circumference at birth, EEG abnormalities, and diaphragmatic paralysis.
Infants With Clinical Findings Consistent With Zika Syndrome
Infants with clinical findings consistent with congenital Zika syndrome who are born to mothers with possible Zika virus exposure in pregnancy should be tested for Zika virus with serum and urine tests. If those tests are negative, and there is no other apparent cause of the symptoms, they should have a CSF sample tested for Zika RNA and IgM Zika antibodies.
By one month, these infants should undergo a head ultrasound and a detailed ophthalmologic exam. The eye exam should pick up any anomalies of the anterior and posterior eye, including microphthalmia, coloboma, intraocular calcifications, optic nerve hypoplasia and atrophy, and macular scarring with focal pigmentary retinal mottling.
By one month, these infants also should undergo auditory brainstem response (ABR) audiometry, especially if the initial newborn hearing screen was done by otoacoustic emissions alone. Zika syndrome can include sensorineural hearing loss, although late-onset hearing loss has not been seen. Therefore, the follow-up ABR previously recommended at four to six months is no longer deemed necessary.
A comprehensive neurologic exam also is recommended. Seizures are sometimes part of Zika syndrome, but infants can also have subclinical EEG abnormalities. Advanced neuroimaging can identify obvious and subtle brain abnormalities, such as cortical thinning, corpus callosum abnormalities, calcifications at the junction of white and gray matter, and ventricular enlargement.
As infants grow, clinicians should be alert for signs of increased intracranial pressure that could signal postnatal hydrocephalus. Diaphragmatic paralysis also has been seen; it manifests as respiratory distress. Dysphagia that interferes with feeding can develop as well.
“The follow-up care of [these infants] requires a multidisciplinary team and an established medical home to facilitate the coordination of care and ensure that abnormal findings are addressed,” said Dr. Adebanjo and colleagues.
Asymptomatic Infants of Mothers With Possible Infection
Infants without clinical findings born to mothers with laboratory evidence of possible Zika virus infection during pregnancy should have the same early head ultrasound, hearing, and eye exams as those with clinical findings. All of these infants also should be tested for Zika virus just as those with clinical findings should be.
If tests are positive, these infants should have all the investigations and follow-up recommended for babies with clinical findings. If laboratory testing is negative, and clinical findings are normal, Zika infection is highly unlikely, and the infants can receive routine care. Clinicians and parents should be on the lookout, however, for new symptoms that might suggest postnatal Zika syndrome.
Asymptomatic Infants Whose Mothers Had Unconfirmed Zika Exposure
Infants without clinical findings consistent with congenital Zika syndrome born to mothers with possible Zika virus exposure in pregnancy, but without laboratory evidence of possible Zika virus infection during pregnancy, constitute a large group. Some women, for example, are never tested during pregnancy, and others have false negative test results. “Because the latter issues are not easily discerned, all mothers with possible exposure to Zika virus during pregnancy who do not have laboratory evidence of possible Zika virus infection, including those who tested negative with currently available technology, should be considered in this group,” said Dr. Adebanjo and colleagues.
The CDC do not recommend further Zika evaluation for these infants unless additional testing confirms maternal infection. For older infants, parents and clinicians should decide together whether further evaluations would be helpful. “If findings consistent with congenital Zika syndrome are identified at any time, referrals to the appropriate specialists should be made, and subsequent evaluation should follow recommendations for infants with clinical findings consistent with congenital Zika syndrome,” said the authors.
The CDC also reiterated their special recommendations for infants who had a prenatal diagnosis of Zika infection. For now, these recommendations remain unchanged, although “as more data become available, understanding of the diagnostic role of prenatal ultrasound and amniocentesis … will improve, and guidance will be updated.”
The optimal timing for a Zika diagnostic ultrasound is uncertain. The CDC recommend that serial ultrasounds be performed every three to four weeks for women with laboratory-confirmed prenatal Zika exposure. Women with possible exposure need only routine ultrasound screenings.
While Zika RNA has been identified in amniotic fluid, there is no consensus on the value of amniocentesis as a prenatal diagnostic tool. Investigations of serial amniocentesis suggest that viral shedding into the amniotic fluid might be transient. If amniocentesis is performed for other reasons, Zika nucleic acid testing can be incorporated.
A shared decision-making process about screening is key, said Dr. Adebanjo and colleagues. “For example, serial ultrasound examinations might be inconvenient, unpleasant, and expensive, and might prompt unnecessary interventions; amniocentesis carries additional known risks such as fetal loss. These potential harms of prenatal screening for congenital Zika syndrome might outweigh the clinical benefits for some patients; therefore, these decisions should be individualized.”
—Michele G. Sullivan
Suggested Reading
Adebanjo T, Godfred-Cato S, Viens L, et al. Update: Interim guidance for the diagnosis, evaluation, and management of infants with possible congenital Zika virus infection - United States, October 2017. MMWR Morb Mortal Wkly Rep. 2017;66(41):1089-1099.
Prenatal methadone maintenance linked to poorer child neurodevelopment
SAN FRANCISCO – Infants born to mothers receiving methadone maintenance treatment show poorer-than-average neurodevelopment outcomes, a retrospective study found.
Delays or difficulties in motor abilities appeared first in these children, followed by evidence of cognitive problems in their second year of life, reported Cristina Borradori Tolsa, MD, of University Hospital, Geneva.
“Higher methadone doses during pregnancy can have a detrimental effect on neonatal characteristics and children’s psychomotor development,” Dr. Borradori Tolsa said at the Pediatric Academic Societies meeting. She noted the need for long-term follow-up of children prenatally exposed to methadone maintenance therapy to evaluate their cognitive abilities and school readiness at preschool ages.
Only 38% of the women had exclusively used methadone, while the other 62% had used a variety of substances, including cocaine, alcohol, benzodiazepine, marijuana, and antidepressants. The women had a low average socioeconomic status based on their level of education and the occupations of the children’s fathers.
The researchers drew children’s development data from their scores on the Bayley Scales of Infant Development, Second Edition (BSID-II), at 6 months and 18-24 months. The BSID-II has an average score of 100 and includes a mental development index for language and cognitive development, and a psychomotor development index to assess fine and gross motor skills.
At age 6 months, 75% of the 40 children assessed showed some level of motor skills delay, and 33% had a moderate to severe delay in psychomotor skills. A quarter had no delay at all (a score of at least 85). The average psychomotor score at 6 months was 76, and the average cognitive score was 88. Most of the children (60%) did, however, show mental development within the normal range at 6 months.
By the age of 18-24 months, half of the 36 children assessed showed no motor delays, and half showed no cognitive delays. One in five (20%) showed a moderate to severe psychomotor delay, and 14% showed a moderate to severe mental development delay. Mild delays in mental development occurred in 36% of the toddlers assessed, and 30% showed mild delays in psychomotor skills.
A dose-response effect was seen with mothers’ higher doses of methadone at birth and their children’s psychomotor scores at 6 months. No similar association existed for mental development, and the psychomotor association disappeared by 18-24 months. At this older age, however, 68% of children born to mothers taking a high dose of methadone showed cognitive delays, compared with 29% of children born to mothers on a low dose.
Although no differences were seen in newborns’ average gestational age (an average of 37.8 weeks overall) or birth weight between the high-dose and low-dose methadone groups, infants born to mothers with high doses were more likely to be small for gestational age (P = .01) and to need longer treatment duration for neonatal abstinence syndrome (NAS) (P = .03). Overall, 44% of the newborns were small for gestational age, 28% were born microcephalic, and all but three required pharmacologic treatment for NAS. NAS treatment lasted an average 54 days for the cohort, and the average hospital stay for the babies was 76 days.
The researchers did not report having any external funding or relevant financial disclosures.
SAN FRANCISCO – Infants born to mothers receiving methadone maintenance treatment show poorer-than-average neurodevelopment outcomes, a retrospective study found.
Delays or difficulties in motor abilities appeared first in these children, followed by evidence of cognitive problems in their second year of life, reported Cristina Borradori Tolsa, MD, of University Hospital, Geneva.
“Higher methadone doses during pregnancy can have a detrimental effect on neonatal characteristics and children’s psychomotor development,” Dr. Borradori Tolsa said at the Pediatric Academic Societies meeting. She noted the need for long-term follow-up of children prenatally exposed to methadone maintenance therapy to evaluate their cognitive abilities and school readiness at preschool ages.
Only 38% of the women had exclusively used methadone, while the other 62% had used a variety of substances, including cocaine, alcohol, benzodiazepine, marijuana, and antidepressants. The women had a low average socioeconomic status based on their level of education and the occupations of the children’s fathers.
The researchers drew children’s development data from their scores on the Bayley Scales of Infant Development, Second Edition (BSID-II), at 6 months and 18-24 months. The BSID-II has an average score of 100 and includes a mental development index for language and cognitive development, and a psychomotor development index to assess fine and gross motor skills.
At age 6 months, 75% of the 40 children assessed showed some level of motor skills delay, and 33% had a moderate to severe delay in psychomotor skills. A quarter had no delay at all (a score of at least 85). The average psychomotor score at 6 months was 76, and the average cognitive score was 88. Most of the children (60%) did, however, show mental development within the normal range at 6 months.
By the age of 18-24 months, half of the 36 children assessed showed no motor delays, and half showed no cognitive delays. One in five (20%) showed a moderate to severe psychomotor delay, and 14% showed a moderate to severe mental development delay. Mild delays in mental development occurred in 36% of the toddlers assessed, and 30% showed mild delays in psychomotor skills.
A dose-response effect was seen with mothers’ higher doses of methadone at birth and their children’s psychomotor scores at 6 months. No similar association existed for mental development, and the psychomotor association disappeared by 18-24 months. At this older age, however, 68% of children born to mothers taking a high dose of methadone showed cognitive delays, compared with 29% of children born to mothers on a low dose.
Although no differences were seen in newborns’ average gestational age (an average of 37.8 weeks overall) or birth weight between the high-dose and low-dose methadone groups, infants born to mothers with high doses were more likely to be small for gestational age (P = .01) and to need longer treatment duration for neonatal abstinence syndrome (NAS) (P = .03). Overall, 44% of the newborns were small for gestational age, 28% were born microcephalic, and all but three required pharmacologic treatment for NAS. NAS treatment lasted an average 54 days for the cohort, and the average hospital stay for the babies was 76 days.
The researchers did not report having any external funding or relevant financial disclosures.
SAN FRANCISCO – Infants born to mothers receiving methadone maintenance treatment show poorer-than-average neurodevelopment outcomes, a retrospective study found.
Delays or difficulties in motor abilities appeared first in these children, followed by evidence of cognitive problems in their second year of life, reported Cristina Borradori Tolsa, MD, of University Hospital, Geneva.
“Higher methadone doses during pregnancy can have a detrimental effect on neonatal characteristics and children’s psychomotor development,” Dr. Borradori Tolsa said at the Pediatric Academic Societies meeting. She noted the need for long-term follow-up of children prenatally exposed to methadone maintenance therapy to evaluate their cognitive abilities and school readiness at preschool ages.
Only 38% of the women had exclusively used methadone, while the other 62% had used a variety of substances, including cocaine, alcohol, benzodiazepine, marijuana, and antidepressants. The women had a low average socioeconomic status based on their level of education and the occupations of the children’s fathers.
The researchers drew children’s development data from their scores on the Bayley Scales of Infant Development, Second Edition (BSID-II), at 6 months and 18-24 months. The BSID-II has an average score of 100 and includes a mental development index for language and cognitive development, and a psychomotor development index to assess fine and gross motor skills.
At age 6 months, 75% of the 40 children assessed showed some level of motor skills delay, and 33% had a moderate to severe delay in psychomotor skills. A quarter had no delay at all (a score of at least 85). The average psychomotor score at 6 months was 76, and the average cognitive score was 88. Most of the children (60%) did, however, show mental development within the normal range at 6 months.
By the age of 18-24 months, half of the 36 children assessed showed no motor delays, and half showed no cognitive delays. One in five (20%) showed a moderate to severe psychomotor delay, and 14% showed a moderate to severe mental development delay. Mild delays in mental development occurred in 36% of the toddlers assessed, and 30% showed mild delays in psychomotor skills.
A dose-response effect was seen with mothers’ higher doses of methadone at birth and their children’s psychomotor scores at 6 months. No similar association existed for mental development, and the psychomotor association disappeared by 18-24 months. At this older age, however, 68% of children born to mothers taking a high dose of methadone showed cognitive delays, compared with 29% of children born to mothers on a low dose.
Although no differences were seen in newborns’ average gestational age (an average of 37.8 weeks overall) or birth weight between the high-dose and low-dose methadone groups, infants born to mothers with high doses were more likely to be small for gestational age (P = .01) and to need longer treatment duration for neonatal abstinence syndrome (NAS) (P = .03). Overall, 44% of the newborns were small for gestational age, 28% were born microcephalic, and all but three required pharmacologic treatment for NAS. NAS treatment lasted an average 54 days for the cohort, and the average hospital stay for the babies was 76 days.
The researchers did not report having any external funding or relevant financial disclosures.
AT PAS 17
Key clinical point:
Major finding: Three-fourths of methadone-exposed infants showed psychomotor delays at 6 months, and 50% showed cognitive delays and/or psychomotor delays at 18-24 months.
Data source: A retrospective analysis of neurodevelopment scores of children born to 61 mothers in Geneva who received methadone maintenance therapy during pregnancy.
Disclosures: The researchers did not report having any external funding or relevant financial disclosures.
ENDEAR Study Demonstrates Efficacy of Nusinersen in Infants With Spinal Muscular Atrophy
BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA. 
SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.
The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.
Study Design
Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.
Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.
Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).
The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.
ENDEAR Final Results
At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.
Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.
Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.
The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.
Good News, Bad News
Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”
—Glenn S. Williams
Suggested Reading
Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026.
BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA.
SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.
The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.
Study Design
Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.
Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.
Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).
The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.
ENDEAR Final Results
At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.
Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.
Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.
The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.
Good News, Bad News
Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”
—Glenn S. Williams
Suggested Reading
Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026.
BOSTON—Infants with spinal muscular atrophy (SMA) type 1 who were treated with nusinersen demonstrated clinically and statistically significant gains across multiple efficacy end points, according to a report presented at the 69th Annual Meeting of the American Academy of Neurology. Nancy L. Kuntz, MD, an attending physician at the Ann and Robert H. Lurie Children’s Hospital of Chicago, on behalf of the ENDEAR Study Group, reported the final results of the phase III ENDEAR study assessing efficacy and safety of nusinersen in infants with SMA.
SMA is a rare, debilitating, autosomal recessive neuromuscular disorder causing varying degrees of weakness. The disease is caused by insufficient levels of SMN protein. Nusinersen is an antisense oligonucleotide that promotes the production of full-length SMN protein.
The ENDEAR study was a phase III, randomized, double-blind, sham-procedure controlled 13-month study to assess the efficacy and safety of nusinersen in infants with SMA. The ENDEAR study had an interim efficacy analysis in September of 2016. This analysis showed that the primary end point—motor milestone response—was positive in 41% of nusinersen-treated infants, and information was submitted to the FDA. Under priority review, Spinraza (nusinersen) was approved for the treatment of SMA in pediatric and adult patients by the FDA on December 23, 2016.
Study Design
Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2:1) to receive intrathecal nusinersen (12-mg scaled equivalent dose) or sham procedure. For both groups, four doses were given over two months, on days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.
Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies, onset of SMA symptoms at younger than 6 months, and no hypoxemia at baseline screening at age 7 months or younger. A total of 122 infants were enrolled.
Primary end points included proportion of modified section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score in kicking ability, or ≥ 1-point increase in head control, rolling, sitting, crawling, standing, or walking] than worsening) and event-free survival (time to death or permanent ventilation). Secondary end points included percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) responders (≥ 4-point increase), overall survival, and percentage of peroneal nerve compound muscle action potential (CMAP) responders (amplitude ≥ 1 mV).
The preplanned interim efficacy analysis was triggered when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor milestone response—was positive, the study was ended, and all of the infants were transferred into the open-label extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed at the ENDEAR interim analysis. With further analysis now complete, Dr. Kuntz presented the end-of-study data set.
ENDEAR Final Results
At the end of the study, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control responders (51% vs 0%), demonstrating continued improvement over the previous interim analysis (41% vs 0%). In the nusinersen-treated group, 22% of infants developed full head control, 10% of the infants developed the ability to independently roll from supine to prone positions, 8% developed independent sitting, with half of those being able to sit and pivot, and one infant was able to stand with minimal to moderate support.
Looking at change over time, the improvement in HINE motor milestone scores seen in ENDEAR matches the trajectory seen in a previous open-label trial. Patients in the previous trial have now been followed for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with presymptomatic SMA who were identified and treated within the first six weeks of life showed improvements in the rate and the range of their motor skills that were much greater than those in the other groups, suggesting that early treatment makes a difference.
Additional analyses included event-free survival, overall survival, CHOP INTEND score, peroneal nerve CMAP response, and need for mechanical ventilation. A significant nusinersen treatment benefit was seen with regard to event-free survival (hazard ratio = 0.530) and overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive at the end of the study, compared with 32% of controls. For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36% versus 5% were CMAP responders. The risk of permanent ventilation was 34% lower in the nusinersen-treated group. Over the course of the study, 31% of the nusinersen-treated infants required permanent ventilation, defined as at least 16 hours per day, compared with 48% of the control infants.
The ENDEAR study was supported by Ionis Pharmaceuticals and Biogen.
Good News, Bad News
Following Dr. Kuntz’s plenary presentation of the ENDEAR study results, Charlotte J. Sumner, MD, Associate Professor of Neurology at Johns Hopkins University in Baltimore, served as the discussant. While Dr. Sumner praised the study findings and the breakthrough they represent, she did point out the staggering cost of the drug. At about $120,000 per dose, the price “has raised issues about insurance approval and reimbursement and raises concerns about delays
to treatment initiation and institutional risk,” she said. “But I would say that despite these challenges, well over 100 patients have already been dosed commercially at very different ages, and this is very promising that we will be able to deliver this drug in a widespread way.”
—Glenn S. Williams
Suggested Reading
Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet. 2016;388(10063):3017-3026.
Buprenorphine is an alternative to morphine in treating NAS
SAN FRANCISCO – The phase III, single-center Blinded Buprenorphine or Neonatal Morphine Solution (BBORN) clinical trial has established the efficacy of buprenorphine as an alternative to morphine for treatment of newborns with neonatal abstinence syndrome (NAS).
The strategy cuts the treatment time needed to relieve the withdrawal symptoms of the infants by nearly half, the researchers reported. The study results, presented at the Pediatric Academic Societies meeting, were simultaneously published in the New England Journal of Medicine (2017. doi: 10.1056/NEJMoa1614835).
“For those infants who ultimately require pharmacologic treatment, the BBORN trial demonstrated that buprenorphine has similar safety and improved efficacy in length of treatment and length of stay compared to morphine, which is used in 80% of neonatal intensive care units,” said Walter K. Kraft, MD, of Thomas Jefferson University, Philadelphia,.
In the trial, 63 term infants (greater than and equal to 37 weeks of gestation) exposed to opioids prior to birth and who displayed signs of NAS were randomized to receive sublingual buprenorphine or oral morphine. Prior exposure to benzodiazepine in the 30 days before birth, medical or neurologic illness, and elevated bilirubin were grounds for exclusion.
The primary endpoint was the length of treatment needed to deal with the withdrawal symptoms. Secondary endpoints included length of hospitalization, need for supplementary treatment with phenobarbital, and safety.
The groups were comparable at baseline, with the exception of median gestational age in the buprenorphine group (38.5 vs. 39.0 weeks, P = .03). Most of the infants were white. Almost all mothers were on maintenance methadone therapy and almost all were current smokers. Thirty-three infants were randomized to receive buprenorphine. Three withdrew and were treated with open-label morphine. Thirty infants received morphine, with two withdrawing to the open-label treatment.
Those receiving buprenorphine displayed significantly shorter median duration of treatment (15 vs. 28 days) and median length of hospital stay (21 vs. 33 days) (both P less than .001). The use of supplemental phenobarbital was similar in both groups.
Occurrence of adverse events was similar, with 13 events in 7 infants in the buprenorphine group and 10 events in 8 infants in the morphine group. One serious event occurred in each group; neither was treatment related.
“The trial only proves that buprenorphine works but does not answer how. We suspect a long half-life is a part of the answer, though methadone also has a long half-life. We have not compared buprenorphine to methadone for treatment of infants with neonatal abstinence syndrome. We conjecture that as a partial agonist, weaning may be smoother. In our trial, it was a shorter wean time, rather than quicker control of symptoms, in which buprenorphine was more effective than morphine. Buprenorphine has effects on other receptors, but it is very unclear if this added to efficacy relative to morphine,” explained Dr. Kraft.
“Regarding mechanism, it is believed that the somatic (as opposed to the drug craving) symptoms of opiate withdrawal in the adult arise from areas of the brainstem called the locus coeruleus and periaqueductal gray, which express opiate receptors. These areas are undergoing major developmental changes in utero and at the time of birth. Therefore, although we hypothesize that the withdrawal symptoms in the infants are likely arising from the same regions, it has not been proven, and is actually something we are investigating in rodent models,” explained the study’s main author, Michelle Ehrlich, MD, of Icahn School of Medicine at Mount Sinai, New York.
While the trial’s findings presented at PAS 17 are an advance in the armamentarium of care for NAS, the researchers are adamant that the approach should not be seen as a stand-alone treatment.
“I would stress than an approach to treatment of neonatal abstinence syndrome most importantly be multidisciplinary and use a uniform institutional protocol. For example, there should be standardization of Finnegan scoring with continuous quality improvement. All babies should have nonpharmacologic treatment of breastfeeding, rooming in, and minimization of excessive stimuli,” explained Dr. Kraft.
Next steps include clarifying the pharmacokinetics to optimize the dose, and to assess the influence of buprenorphine on neurobehavior. “We suspect the mechanism of action to be similar to that of adults. However, how the biology of neonatal abstinence syndrome differs from opioid withdrawal of adults is not known and [is] an area in need of more investigation. We did collect pharmacokinetic samples, and these data are currently being analyzed,” said Dr. Kraft.
Thomas Jefferson University sponsored the study, which was funded by the National Institute on Drug Abuse. Dr. Kraft reported serving as an unpaid consultant to Chiesi Farmaceutici S.p.A. Dr. Ehrlich disclosed receipt of buprenorphine from Indivior for the study and grants from NIDA.
SAN FRANCISCO – The phase III, single-center Blinded Buprenorphine or Neonatal Morphine Solution (BBORN) clinical trial has established the efficacy of buprenorphine as an alternative to morphine for treatment of newborns with neonatal abstinence syndrome (NAS).
The strategy cuts the treatment time needed to relieve the withdrawal symptoms of the infants by nearly half, the researchers reported. The study results, presented at the Pediatric Academic Societies meeting, were simultaneously published in the New England Journal of Medicine (2017. doi: 10.1056/NEJMoa1614835).
“For those infants who ultimately require pharmacologic treatment, the BBORN trial demonstrated that buprenorphine has similar safety and improved efficacy in length of treatment and length of stay compared to morphine, which is used in 80% of neonatal intensive care units,” said Walter K. Kraft, MD, of Thomas Jefferson University, Philadelphia,.
In the trial, 63 term infants (greater than and equal to 37 weeks of gestation) exposed to opioids prior to birth and who displayed signs of NAS were randomized to receive sublingual buprenorphine or oral morphine. Prior exposure to benzodiazepine in the 30 days before birth, medical or neurologic illness, and elevated bilirubin were grounds for exclusion.
The primary endpoint was the length of treatment needed to deal with the withdrawal symptoms. Secondary endpoints included length of hospitalization, need for supplementary treatment with phenobarbital, and safety.
The groups were comparable at baseline, with the exception of median gestational age in the buprenorphine group (38.5 vs. 39.0 weeks, P = .03). Most of the infants were white. Almost all mothers were on maintenance methadone therapy and almost all were current smokers. Thirty-three infants were randomized to receive buprenorphine. Three withdrew and were treated with open-label morphine. Thirty infants received morphine, with two withdrawing to the open-label treatment.
Those receiving buprenorphine displayed significantly shorter median duration of treatment (15 vs. 28 days) and median length of hospital stay (21 vs. 33 days) (both P less than .001). The use of supplemental phenobarbital was similar in both groups.
Occurrence of adverse events was similar, with 13 events in 7 infants in the buprenorphine group and 10 events in 8 infants in the morphine group. One serious event occurred in each group; neither was treatment related.
“The trial only proves that buprenorphine works but does not answer how. We suspect a long half-life is a part of the answer, though methadone also has a long half-life. We have not compared buprenorphine to methadone for treatment of infants with neonatal abstinence syndrome. We conjecture that as a partial agonist, weaning may be smoother. In our trial, it was a shorter wean time, rather than quicker control of symptoms, in which buprenorphine was more effective than morphine. Buprenorphine has effects on other receptors, but it is very unclear if this added to efficacy relative to morphine,” explained Dr. Kraft.
“Regarding mechanism, it is believed that the somatic (as opposed to the drug craving) symptoms of opiate withdrawal in the adult arise from areas of the brainstem called the locus coeruleus and periaqueductal gray, which express opiate receptors. These areas are undergoing major developmental changes in utero and at the time of birth. Therefore, although we hypothesize that the withdrawal symptoms in the infants are likely arising from the same regions, it has not been proven, and is actually something we are investigating in rodent models,” explained the study’s main author, Michelle Ehrlich, MD, of Icahn School of Medicine at Mount Sinai, New York.
While the trial’s findings presented at PAS 17 are an advance in the armamentarium of care for NAS, the researchers are adamant that the approach should not be seen as a stand-alone treatment.
“I would stress than an approach to treatment of neonatal abstinence syndrome most importantly be multidisciplinary and use a uniform institutional protocol. For example, there should be standardization of Finnegan scoring with continuous quality improvement. All babies should have nonpharmacologic treatment of breastfeeding, rooming in, and minimization of excessive stimuli,” explained Dr. Kraft.
Next steps include clarifying the pharmacokinetics to optimize the dose, and to assess the influence of buprenorphine on neurobehavior. “We suspect the mechanism of action to be similar to that of adults. However, how the biology of neonatal abstinence syndrome differs from opioid withdrawal of adults is not known and [is] an area in need of more investigation. We did collect pharmacokinetic samples, and these data are currently being analyzed,” said Dr. Kraft.
Thomas Jefferson University sponsored the study, which was funded by the National Institute on Drug Abuse. Dr. Kraft reported serving as an unpaid consultant to Chiesi Farmaceutici S.p.A. Dr. Ehrlich disclosed receipt of buprenorphine from Indivior for the study and grants from NIDA.
SAN FRANCISCO – The phase III, single-center Blinded Buprenorphine or Neonatal Morphine Solution (BBORN) clinical trial has established the efficacy of buprenorphine as an alternative to morphine for treatment of newborns with neonatal abstinence syndrome (NAS).
The strategy cuts the treatment time needed to relieve the withdrawal symptoms of the infants by nearly half, the researchers reported. The study results, presented at the Pediatric Academic Societies meeting, were simultaneously published in the New England Journal of Medicine (2017. doi: 10.1056/NEJMoa1614835).
“For those infants who ultimately require pharmacologic treatment, the BBORN trial demonstrated that buprenorphine has similar safety and improved efficacy in length of treatment and length of stay compared to morphine, which is used in 80% of neonatal intensive care units,” said Walter K. Kraft, MD, of Thomas Jefferson University, Philadelphia,.
In the trial, 63 term infants (greater than and equal to 37 weeks of gestation) exposed to opioids prior to birth and who displayed signs of NAS were randomized to receive sublingual buprenorphine or oral morphine. Prior exposure to benzodiazepine in the 30 days before birth, medical or neurologic illness, and elevated bilirubin were grounds for exclusion.
The primary endpoint was the length of treatment needed to deal with the withdrawal symptoms. Secondary endpoints included length of hospitalization, need for supplementary treatment with phenobarbital, and safety.
The groups were comparable at baseline, with the exception of median gestational age in the buprenorphine group (38.5 vs. 39.0 weeks, P = .03). Most of the infants were white. Almost all mothers were on maintenance methadone therapy and almost all were current smokers. Thirty-three infants were randomized to receive buprenorphine. Three withdrew and were treated with open-label morphine. Thirty infants received morphine, with two withdrawing to the open-label treatment.
Those receiving buprenorphine displayed significantly shorter median duration of treatment (15 vs. 28 days) and median length of hospital stay (21 vs. 33 days) (both P less than .001). The use of supplemental phenobarbital was similar in both groups.
Occurrence of adverse events was similar, with 13 events in 7 infants in the buprenorphine group and 10 events in 8 infants in the morphine group. One serious event occurred in each group; neither was treatment related.
“The trial only proves that buprenorphine works but does not answer how. We suspect a long half-life is a part of the answer, though methadone also has a long half-life. We have not compared buprenorphine to methadone for treatment of infants with neonatal abstinence syndrome. We conjecture that as a partial agonist, weaning may be smoother. In our trial, it was a shorter wean time, rather than quicker control of symptoms, in which buprenorphine was more effective than morphine. Buprenorphine has effects on other receptors, but it is very unclear if this added to efficacy relative to morphine,” explained Dr. Kraft.
“Regarding mechanism, it is believed that the somatic (as opposed to the drug craving) symptoms of opiate withdrawal in the adult arise from areas of the brainstem called the locus coeruleus and periaqueductal gray, which express opiate receptors. These areas are undergoing major developmental changes in utero and at the time of birth. Therefore, although we hypothesize that the withdrawal symptoms in the infants are likely arising from the same regions, it has not been proven, and is actually something we are investigating in rodent models,” explained the study’s main author, Michelle Ehrlich, MD, of Icahn School of Medicine at Mount Sinai, New York.
While the trial’s findings presented at PAS 17 are an advance in the armamentarium of care for NAS, the researchers are adamant that the approach should not be seen as a stand-alone treatment.
“I would stress than an approach to treatment of neonatal abstinence syndrome most importantly be multidisciplinary and use a uniform institutional protocol. For example, there should be standardization of Finnegan scoring with continuous quality improvement. All babies should have nonpharmacologic treatment of breastfeeding, rooming in, and minimization of excessive stimuli,” explained Dr. Kraft.
Next steps include clarifying the pharmacokinetics to optimize the dose, and to assess the influence of buprenorphine on neurobehavior. “We suspect the mechanism of action to be similar to that of adults. However, how the biology of neonatal abstinence syndrome differs from opioid withdrawal of adults is not known and [is] an area in need of more investigation. We did collect pharmacokinetic samples, and these data are currently being analyzed,” said Dr. Kraft.
Thomas Jefferson University sponsored the study, which was funded by the National Institute on Drug Abuse. Dr. Kraft reported serving as an unpaid consultant to Chiesi Farmaceutici S.p.A. Dr. Ehrlich disclosed receipt of buprenorphine from Indivior for the study and grants from NIDA.
AT PAS 17
Key clinical point:
Major finding: Buprenorphine reduced median length of treatment (15 vs. 28 days, P less than .001) and median length of stay (21 vs. 34.5 days, P less than .001), compared with morphine.
Data source: Double-blind, double-dummy, single-site, randomized clinical trial (NCT01452789).
Disclosures: Thomas Jefferson University sponsored the study, which was funded by the National Institute on Drug Abuse. Dr. Kraft reported serving as an unpaid consultant to Chiesi Farmaceutici S.p.A. Dr. Ehrlich disclosed receipt of buprenorphine from Indivior for the study and grants from NIDA.
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Smoking During Pregnancy May Damage Offspring’s Retinal Nerve Fiber Layer
Retinal nerve fiber layer defects are a defining feature of optic neuropathies and have been implicated in several neurodegenerative disorders, including multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. Both maternal smoking during pregnancy and low birth weight have been implicated in impaired development of the retina.
The Copenhagen Child Cohort 2000 Eye Study
Mr. Ashina and colleagues sought to investigate the associations of maternal smoking during pregnancy and low birth weight with retinal nerve fiber layer thickness in preadolescent children. They examined data from a prospective, population-based, birth cohort study that included all children (n = 6,090) born in 2000 in Copenhagen. Maternal smoking data were collected through parental interviews. Birth weight, pregnancy, and medical history data were obtained from the Danish Medical Birth Registry. As a follow-up, the researchers performed eye examinations on 1,406 of these children from May 1, 2011, to October 31, 2012, when the children were age 11 or 12.
Of the 1,406 children in the study, 1,323 were included in the analysis. Mean age was 11.7. Nearly half of the children (47.8%) were boys. The mean retinal nerve fiber layer thickness was 104 mm. In 227 children whose mothers had smoked during pregnancy, the peripapillary retinal nerve fiber layer was 5.7 mm thinner than in children whose mothers had not smoked during pregnancy, after adjusting for age, sex, birth weight, height, body weight, Tanner stage of pubertal development, axial length, and spherical equivalent refractive error. In children with low birth weight (ie, < 2,500 g), the retinal nerve fiber layer was 3.5 mm thinner than in children with normal birth weight, after adjustment for all variables.
“The results of this study add evidence to existing recommendations to avoid smoking during pregnancy and support measures that promote maternal and fetal health,” the researchers said.
A Public Health Message
In an invited commentary that accompanied the study, Christopher Kai-Shun Leung, MD, from the Department of Ophthalmology and Visual Sciences at Hong Kong Eye Hospital and Chinese University of Hong Kong in Kowloon, said that “although a difference of 5 to 6 mm in average circumpapillary retinal nerve fiber layer thickness is unlikely to translate into a detectable difference in visual function in children aged 12 to 13 years, the risk of subsequent development of visual impairment should not be overlooked.” Furthermore, he noted, “whether a thinner retinal nerve fiber layer in the children of mothers who smoked during pregnancy w
—Glenn S. Williams
Suggested Reading
Ashina H, Li XQ, Olsen EM, et al. Association of maternal smoking during pregnancy and birth weight with retinal nerve fiber layer thickness in children aged 11 or 12 years: The Copenhagen Child Cohort 2000 Eye Study. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Leung CK. Evaluation of retinal nerve fiber layer thinning with Fourier-domain optical coherence tomography. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Retinal nerve fiber layer defects are a defining feature of optic neuropathies and have been implicated in several neurodegenerative disorders, including multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. Both maternal smoking during pregnancy and low birth weight have been implicated in impaired development of the retina.
The Copenhagen Child Cohort 2000 Eye Study
Mr. Ashina and colleagues sought to investigate the associations of maternal smoking during pregnancy and low birth weight with retinal nerve fiber layer thickness in preadolescent children. They examined data from a prospective, population-based, birth cohort study that included all children (n = 6,090) born in 2000 in Copenhagen. Maternal smoking data were collected through parental interviews. Birth weight, pregnancy, and medical history data were obtained from the Danish Medical Birth Registry. As a follow-up, the researchers performed eye examinations on 1,406 of these children from May 1, 2011, to October 31, 2012, when the children were age 11 or 12.
Of the 1,406 children in the study, 1,323 were included in the analysis. Mean age was 11.7. Nearly half of the children (47.8%) were boys. The mean retinal nerve fiber layer thickness was 104 mm. In 227 children whose mothers had smoked during pregnancy, the peripapillary retinal nerve fiber layer was 5.7 mm thinner than in children whose mothers had not smoked during pregnancy, after adjusting for age, sex, birth weight, height, body weight, Tanner stage of pubertal development, axial length, and spherical equivalent refractive error. In children with low birth weight (ie, < 2,500 g), the retinal nerve fiber layer was 3.5 mm thinner than in children with normal birth weight, after adjustment for all variables.
“The results of this study add evidence to existing recommendations to avoid smoking during pregnancy and support measures that promote maternal and fetal health,” the researchers said.
A Public Health Message
In an invited commentary that accompanied the study, Christopher Kai-Shun Leung, MD, from the Department of Ophthalmology and Visual Sciences at Hong Kong Eye Hospital and Chinese University of Hong Kong in Kowloon, said that “although a difference of 5 to 6 mm in average circumpapillary retinal nerve fiber layer thickness is unlikely to translate into a detectable difference in visual function in children aged 12 to 13 years, the risk of subsequent development of visual impairment should not be overlooked.” Furthermore, he noted, “whether a thinner retinal nerve fiber layer in the children of mothers who smoked during pregnancy w
—Glenn S. Williams
Suggested Reading
Ashina H, Li XQ, Olsen EM, et al. Association of maternal smoking during pregnancy and birth weight with retinal nerve fiber layer thickness in children aged 11 or 12 years: The Copenhagen Child Cohort 2000 Eye Study. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Leung CK. Evaluation of retinal nerve fiber layer thinning with Fourier-domain optical coherence tomography. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Retinal nerve fiber layer defects are a defining feature of optic neuropathies and have been implicated in several neurodegenerative disorders, including multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. Both maternal smoking during pregnancy and low birth weight have been implicated in impaired development of the retina.
The Copenhagen Child Cohort 2000 Eye Study
Mr. Ashina and colleagues sought to investigate the associations of maternal smoking during pregnancy and low birth weight with retinal nerve fiber layer thickness in preadolescent children. They examined data from a prospective, population-based, birth cohort study that included all children (n = 6,090) born in 2000 in Copenhagen. Maternal smoking data were collected through parental interviews. Birth weight, pregnancy, and medical history data were obtained from the Danish Medical Birth Registry. As a follow-up, the researchers performed eye examinations on 1,406 of these children from May 1, 2011, to October 31, 2012, when the children were age 11 or 12.
Of the 1,406 children in the study, 1,323 were included in the analysis. Mean age was 11.7. Nearly half of the children (47.8%) were boys. The mean retinal nerve fiber layer thickness was 104 mm. In 227 children whose mothers had smoked during pregnancy, the peripapillary retinal nerve fiber layer was 5.7 mm thinner than in children whose mothers had not smoked during pregnancy, after adjusting for age, sex, birth weight, height, body weight, Tanner stage of pubertal development, axial length, and spherical equivalent refractive error. In children with low birth weight (ie, < 2,500 g), the retinal nerve fiber layer was 3.5 mm thinner than in children with normal birth weight, after adjustment for all variables.
“The results of this study add evidence to existing recommendations to avoid smoking during pregnancy and support measures that promote maternal and fetal health,” the researchers said.
A Public Health Message
In an invited commentary that accompanied the study, Christopher Kai-Shun Leung, MD, from the Department of Ophthalmology and Visual Sciences at Hong Kong Eye Hospital and Chinese University of Hong Kong in Kowloon, said that “although a difference of 5 to 6 mm in average circumpapillary retinal nerve fiber layer thickness is unlikely to translate into a detectable difference in visual function in children aged 12 to 13 years, the risk of subsequent development of visual impairment should not be overlooked.” Furthermore, he noted, “whether a thinner retinal nerve fiber layer in the children of mothers who smoked during pregnancy w
—Glenn S. Williams
Suggested Reading
Ashina H, Li XQ, Olsen EM, et al. Association of maternal smoking during pregnancy and birth weight with retinal nerve fiber layer thickness in children aged 11 or 12 years: The Copenhagen Child Cohort 2000 Eye Study. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Leung CK. Evaluation of retinal nerve fiber layer thinning with Fourier-domain optical coherence tomography. JAMA Ophthalmol. 2017 March 2 [Epub ahead of print].
Toddlers’ neurodevelopmental deficits linked with maternal diabetes
LAS VEGAS – Children born to obese women with insulin resistance during pregnancy showed significantly impaired neurodevelopment at 2 years of age, compared with children born to obese mothers without insulin resistance in a prospective observational study with 75 pregnant women.
The neurodevelopmental deficits were specific for the domains of motor function and attention, and the deficits correlated with several markers of abnormal glucose and fat metabolism in the insulin-resistant women, Alison G. Cahill, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
“The differences in neurodevelopment appear to not be global but instead specifically affect domains of motor development and attention,” said Dr. Cahill, chief of maternal fetal medicine at Washington University in St. Louis. “These findings are consistent with results from animal studies that suggest certain brain regions are more sensitive than others to metabolic abnormalities” while in utero.
“These are among the first data in humans to characterize the impact of metabolic abnormalities on brain development,” she added.
Dr. Cahill said that results from the lean mothers uniformly matched those from the obese mothers without insulin resistance, and so for brevity she only reported results from the obese control group.
Average gestational age at birth was 37 weeks in the insulin-resistant mothers and 38.7 weeks among the obese mothers without insulin resistance, a significant difference. Birth weight averaged 3,617 g in the mothers with insulin resistance and 3,373 g in the mothers without insulin resistance, a difference that was not statistically significant.
Dr. Cahill and her associates assessed the 2-year-olds with a battery of behavioral and functional assessments. They measured motor function, cognition, and language with the Bayley Scales of Infant and Toddler Development, prespecified as the study’s primary endpoint. They also applied the Modified Checklist for Autism in Toddlers (M-CHAT), as well as the Infant-Toddler Social and Emotional Assessment (ITSEA) to assess competence, externalizing, internalizing, and dysregulation.
The results of these analyses showed statistically significant deficits for the motor composite score on the Bayley assessment and for the competence component of the ITSEA assessment, Dr. Cahill reported. The average composite Bayley motor score was 88 in children from mothers with insulin resistance and 98 in the control children, a statistically significant difference.
Further analyses showed that the motor deficit was primarily in fine motor function, and that motor scores were depressed throughout the entire cohort of children born to mothers with insulin resistance.
Depressed competence scores on the ITSEA assessment reflect attention abnormalities, she explained.
A final analysis examined the correlation between the motor deficits identified and various metabolic tests of fat, glucose, and protein metabolism run on the enrolled mothers during the last weeks of gestation. This showed significant links between depressed motor development and maternal lipolytic rate, plasma free fatty acids, and hepatic glucose output.
This finding “suggests an association between abnormal lipid and glucose metabolism in mothers and aspects of neurodevelopment” in their children, Dr. Cahill said.
Dr. Cahill had no disclosures.
mzoler@frontlinemedcom.com On Twitter @mitchelzoler
LAS VEGAS – Children born to obese women with insulin resistance during pregnancy showed significantly impaired neurodevelopment at 2 years of age, compared with children born to obese mothers without insulin resistance in a prospective observational study with 75 pregnant women.
The neurodevelopmental deficits were specific for the domains of motor function and attention, and the deficits correlated with several markers of abnormal glucose and fat metabolism in the insulin-resistant women, Alison G. Cahill, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
“The differences in neurodevelopment appear to not be global but instead specifically affect domains of motor development and attention,” said Dr. Cahill, chief of maternal fetal medicine at Washington University in St. Louis. “These findings are consistent with results from animal studies that suggest certain brain regions are more sensitive than others to metabolic abnormalities” while in utero.
“These are among the first data in humans to characterize the impact of metabolic abnormalities on brain development,” she added.
Dr. Cahill said that results from the lean mothers uniformly matched those from the obese mothers without insulin resistance, and so for brevity she only reported results from the obese control group.
Average gestational age at birth was 37 weeks in the insulin-resistant mothers and 38.7 weeks among the obese mothers without insulin resistance, a significant difference. Birth weight averaged 3,617 g in the mothers with insulin resistance and 3,373 g in the mothers without insulin resistance, a difference that was not statistically significant.
Dr. Cahill and her associates assessed the 2-year-olds with a battery of behavioral and functional assessments. They measured motor function, cognition, and language with the Bayley Scales of Infant and Toddler Development, prespecified as the study’s primary endpoint. They also applied the Modified Checklist for Autism in Toddlers (M-CHAT), as well as the Infant-Toddler Social and Emotional Assessment (ITSEA) to assess competence, externalizing, internalizing, and dysregulation.
The results of these analyses showed statistically significant deficits for the motor composite score on the Bayley assessment and for the competence component of the ITSEA assessment, Dr. Cahill reported. The average composite Bayley motor score was 88 in children from mothers with insulin resistance and 98 in the control children, a statistically significant difference.
Further analyses showed that the motor deficit was primarily in fine motor function, and that motor scores were depressed throughout the entire cohort of children born to mothers with insulin resistance.
Depressed competence scores on the ITSEA assessment reflect attention abnormalities, she explained.
A final analysis examined the correlation between the motor deficits identified and various metabolic tests of fat, glucose, and protein metabolism run on the enrolled mothers during the last weeks of gestation. This showed significant links between depressed motor development and maternal lipolytic rate, plasma free fatty acids, and hepatic glucose output.
This finding “suggests an association between abnormal lipid and glucose metabolism in mothers and aspects of neurodevelopment” in their children, Dr. Cahill said.
Dr. Cahill had no disclosures.
mzoler@frontlinemedcom.com On Twitter @mitchelzoler
LAS VEGAS – Children born to obese women with insulin resistance during pregnancy showed significantly impaired neurodevelopment at 2 years of age, compared with children born to obese mothers without insulin resistance in a prospective observational study with 75 pregnant women.
The neurodevelopmental deficits were specific for the domains of motor function and attention, and the deficits correlated with several markers of abnormal glucose and fat metabolism in the insulin-resistant women, Alison G. Cahill, MD, said at the annual Pregnancy Meeting sponsored by the Society for Maternal-Fetal Medicine.
“The differences in neurodevelopment appear to not be global but instead specifically affect domains of motor development and attention,” said Dr. Cahill, chief of maternal fetal medicine at Washington University in St. Louis. “These findings are consistent with results from animal studies that suggest certain brain regions are more sensitive than others to metabolic abnormalities” while in utero.
“These are among the first data in humans to characterize the impact of metabolic abnormalities on brain development,” she added.
Dr. Cahill said that results from the lean mothers uniformly matched those from the obese mothers without insulin resistance, and so for brevity she only reported results from the obese control group.
Average gestational age at birth was 37 weeks in the insulin-resistant mothers and 38.7 weeks among the obese mothers without insulin resistance, a significant difference. Birth weight averaged 3,617 g in the mothers with insulin resistance and 3,373 g in the mothers without insulin resistance, a difference that was not statistically significant.
Dr. Cahill and her associates assessed the 2-year-olds with a battery of behavioral and functional assessments. They measured motor function, cognition, and language with the Bayley Scales of Infant and Toddler Development, prespecified as the study’s primary endpoint. They also applied the Modified Checklist for Autism in Toddlers (M-CHAT), as well as the Infant-Toddler Social and Emotional Assessment (ITSEA) to assess competence, externalizing, internalizing, and dysregulation.
The results of these analyses showed statistically significant deficits for the motor composite score on the Bayley assessment and for the competence component of the ITSEA assessment, Dr. Cahill reported. The average composite Bayley motor score was 88 in children from mothers with insulin resistance and 98 in the control children, a statistically significant difference.
Further analyses showed that the motor deficit was primarily in fine motor function, and that motor scores were depressed throughout the entire cohort of children born to mothers with insulin resistance.
Depressed competence scores on the ITSEA assessment reflect attention abnormalities, she explained.
A final analysis examined the correlation between the motor deficits identified and various metabolic tests of fat, glucose, and protein metabolism run on the enrolled mothers during the last weeks of gestation. This showed significant links between depressed motor development and maternal lipolytic rate, plasma free fatty acids, and hepatic glucose output.
This finding “suggests an association between abnormal lipid and glucose metabolism in mothers and aspects of neurodevelopment” in their children, Dr. Cahill said.
Dr. Cahill had no disclosures.
mzoler@frontlinemedcom.com On Twitter @mitchelzoler
Key clinical point:
Major finding: The Bayley motor scale score averaged 88 in children from insulin-resistant mothers and 98 when no insulin resistance existed.
Data source: Prospective, single-center observational study with 75 pregnant women.
Disclosures: Dr. Cahill had no disclosures.
Recognizing Congenital Zika Syndrome
VANCOUVER—Infants infected with Zika virus in utero may develop a syndrome characterized by brain volume loss, intracerebral calcifications, and spasticity. They may develop dyskinesia or seizures after several months, and a subset of children has severe arthrogryposis.
And although microcephaly at birth is common, infants may have a normal head size at birth, but develop postnatal microcephaly or other neurologic symptoms at six months, according to research described at the 45th Annual Meeting of the Child Neurology Society.
“The spectrum of congenital Zika syndrome is expanding as we come to understand it better,” said William B. Dobyns, MD, Professor of Pediatrics at the University of Washington in Seattle and a faculty member at the Center for Integrative Brain Research at Seattle Children’s Research Institute. “We all need to stop calling this microcephaly. This is much more than that. This is the congenital Zika syndrome.” 
Zika virus is trophic for neural stem cells, and the first reports of microcephaly associated with prenatal Zika virus infection came from Brazil in January 2016. In the US, mosquitoes that transmit Zika virus, Aedes aegypti and albopictus, are present year round in Florida and seasonally in about a quarter of the states. “It is pretty clear that it will be coming.… We need to take precautions until treatments or preventives are available,” he said. In addition, child neurologists need to be able to recognize congenital Zika syndrome. “It is entirely possible for us to do so,” Dr. Dobyns said. “You do not even need viral titers in the more classically affected children.”
A Case Series of 57 Children
Dr. Dobyns worked with André Pessoa, MD, a child neurologist at Hospital Infantil Albert Sabin in Fortaleza, Brazil, and other neurologists in the region to compile data on a series of 57 children with congenital microcephaly and presumed or proven Zika exposure of the mothers during pregnancy. Microcephaly was defined as occipitofrontal head circumference of at least two standard deviations below the mean.
About half of the children had a bony protuberance of the occipital bone, known as an occipital shelf, Dr. Dobyns said. This feature occurs when the fetal brain, instead of growing and pushing out the skull plates, is severely injured and shrinks. The frontal and parietal bones, but not the occipital bone, collapse over the injured brain.
Almost all of the children had prominent calcifications in the brain. Unlike in children infected with cytomegalovirus, periventricular calcifications are the exception in children infected with Zika virus. Researchers observed subcortical or cortical calcifications on CT in 51 of the 57 children infected with Zika virus and basal ganglia calcifications in 33 of the 57 children.
Furthermore, calcifications with Zika virus infection tend to be diffuse and bilateral, whereas calcifications with cytomegalovirus infection tend to be patchy, Dr. Dobyns said.
All patients had the same general pattern of enlarged extra-axial space, ventriculomegaly, or both, indicating brain volume loss.
About 20% of patients had severe arthrogryposis multiplex congenita, and all of these children had abnormally positioned proximal joints.
Twenty of the children underwent brain MRI. MRI showed an abnormal cortex in all 20 children. The patients appear to have a diffuse cortical malformation that is most consistent with polymicrogyria, Dr. Dobyns said.
Nearly 20% of children in the series had microcephaly between two and three standard deviations below the mean. But 81% had microcephaly of three or more standard deviations below the mean. The mean occipitofrontal head circumference was four standard deviations below the mean.
Neurologic features included spasticity in 94% of the children and severe irritability or tremor in 64% of the children. About 20% had seizures after several months. Some patients had eye abnormalities, including optic nerve pallor, macular atrophy, and strabismus.
“The exam is characteristic,” Dr. Dobyns said. “They all develop a dyskinesia later in the first year of life. They have spastic quadriparesis. They frequently have tremors at birth. They feed poorly. They tend to be irritable and scream all the time. They are starting to have seizures as they get past six months of age.”
As in other studies, data from this series suggest that children whose mothers have a symptomatic illness or are infected earlier in pregnancy may be at higher risk of congenital Zika syndrome.
Infants Without Microcephaly at Birth
Dr. Dobyns presented preliminary data from children who were exposed to Zika virus but did not have microcephaly at birth. These children had most of the same features on exam as children with microcephaly, although the features tended to be less severe. The children started to have seizures after several months. When their head size was measured at six months or older, it fell below the second percentile, meaning that these children had postnatal microcephaly. The children did not have congenital contractures, Dr. Dobyns said.
Vanessa van der Linden, MD, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, Dr. Pessoa, Dr. Dobyns, and colleagues on November 22, 2016, published a description of 13 infants who had evidence of congenital Zika infection but did not have microcephaly at birth. Their report was published online in the CDC’s Morbidity and Mortality Weekly Report. The researchers found that head growth decelerated in all 13 of the infants by as early as age 5 months, and 11 of the infants had microcephaly. The findings suggest that infants exposed to Zika virus prenatally should receive comprehensive medical and developmental follow-up, even in the absence of microcephaly at birth, the investigators said.
That infants with prenatal Zika infection may develop postnatal microcephaly is not surprising, Dr. Dobyns said. Microcephaly, however, remains only one possible symptom of congenital Zika syndrome. “It is a pattern of features seen clinically, on CT scans, and behaviorally that will mark this syndrome,” he said.
—Jake Remaly
Suggested Reading
Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 2016 Nov 3 [Epub ahead of print].
van der Linden V, Pessoa A, Dobyns W, et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth — Brazil. MMWR Morb Mortal Wkly Rep. 22 Nov 2016 [Epub ahead of print].
VANCOUVER—Infants infected with Zika virus in utero may develop a syndrome characterized by brain volume loss, intracerebral calcifications, and spasticity. They may develop dyskinesia or seizures after several months, and a subset of children has severe arthrogryposis.
And although microcephaly at birth is common, infants may have a normal head size at birth, but develop postnatal microcephaly or other neurologic symptoms at six months, according to research described at the 45th Annual Meeting of the Child Neurology Society.
“The spectrum of congenital Zika syndrome is expanding as we come to understand it better,” said William B. Dobyns, MD, Professor of Pediatrics at the University of Washington in Seattle and a faculty member at the Center for Integrative Brain Research at Seattle Children’s Research Institute. “We all need to stop calling this microcephaly. This is much more than that. This is the congenital Zika syndrome.”
Zika virus is trophic for neural stem cells, and the first reports of microcephaly associated with prenatal Zika virus infection came from Brazil in January 2016. In the US, mosquitoes that transmit Zika virus, Aedes aegypti and albopictus, are present year round in Florida and seasonally in about a quarter of the states. “It is pretty clear that it will be coming.… We need to take precautions until treatments or preventives are available,” he said. In addition, child neurologists need to be able to recognize congenital Zika syndrome. “It is entirely possible for us to do so,” Dr. Dobyns said. “You do not even need viral titers in the more classically affected children.”
A Case Series of 57 Children
Dr. Dobyns worked with André Pessoa, MD, a child neurologist at Hospital Infantil Albert Sabin in Fortaleza, Brazil, and other neurologists in the region to compile data on a series of 57 children with congenital microcephaly and presumed or proven Zika exposure of the mothers during pregnancy. Microcephaly was defined as occipitofrontal head circumference of at least two standard deviations below the mean.
About half of the children had a bony protuberance of the occipital bone, known as an occipital shelf, Dr. Dobyns said. This feature occurs when the fetal brain, instead of growing and pushing out the skull plates, is severely injured and shrinks. The frontal and parietal bones, but not the occipital bone, collapse over the injured brain.
Almost all of the children had prominent calcifications in the brain. Unlike in children infected with cytomegalovirus, periventricular calcifications are the exception in children infected with Zika virus. Researchers observed subcortical or cortical calcifications on CT in 51 of the 57 children infected with Zika virus and basal ganglia calcifications in 33 of the 57 children.
Furthermore, calcifications with Zika virus infection tend to be diffuse and bilateral, whereas calcifications with cytomegalovirus infection tend to be patchy, Dr. Dobyns said.
All patients had the same general pattern of enlarged extra-axial space, ventriculomegaly, or both, indicating brain volume loss.
About 20% of patients had severe arthrogryposis multiplex congenita, and all of these children had abnormally positioned proximal joints.
Twenty of the children underwent brain MRI. MRI showed an abnormal cortex in all 20 children. The patients appear to have a diffuse cortical malformation that is most consistent with polymicrogyria, Dr. Dobyns said.
Nearly 20% of children in the series had microcephaly between two and three standard deviations below the mean. But 81% had microcephaly of three or more standard deviations below the mean. The mean occipitofrontal head circumference was four standard deviations below the mean.
Neurologic features included spasticity in 94% of the children and severe irritability or tremor in 64% of the children. About 20% had seizures after several months. Some patients had eye abnormalities, including optic nerve pallor, macular atrophy, and strabismus.
“The exam is characteristic,” Dr. Dobyns said. “They all develop a dyskinesia later in the first year of life. They have spastic quadriparesis. They frequently have tremors at birth. They feed poorly. They tend to be irritable and scream all the time. They are starting to have seizures as they get past six months of age.”
As in other studies, data from this series suggest that children whose mothers have a symptomatic illness or are infected earlier in pregnancy may be at higher risk of congenital Zika syndrome.
Infants Without Microcephaly at Birth
Dr. Dobyns presented preliminary data from children who were exposed to Zika virus but did not have microcephaly at birth. These children had most of the same features on exam as children with microcephaly, although the features tended to be less severe. The children started to have seizures after several months. When their head size was measured at six months or older, it fell below the second percentile, meaning that these children had postnatal microcephaly. The children did not have congenital contractures, Dr. Dobyns said.
Vanessa van der Linden, MD, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, Dr. Pessoa, Dr. Dobyns, and colleagues on November 22, 2016, published a description of 13 infants who had evidence of congenital Zika infection but did not have microcephaly at birth. Their report was published online in the CDC’s Morbidity and Mortality Weekly Report. The researchers found that head growth decelerated in all 13 of the infants by as early as age 5 months, and 11 of the infants had microcephaly. The findings suggest that infants exposed to Zika virus prenatally should receive comprehensive medical and developmental follow-up, even in the absence of microcephaly at birth, the investigators said.
That infants with prenatal Zika infection may develop postnatal microcephaly is not surprising, Dr. Dobyns said. Microcephaly, however, remains only one possible symptom of congenital Zika syndrome. “It is a pattern of features seen clinically, on CT scans, and behaviorally that will mark this syndrome,” he said.
—Jake Remaly
Suggested Reading
Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 2016 Nov 3 [Epub ahead of print].
van der Linden V, Pessoa A, Dobyns W, et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth — Brazil. MMWR Morb Mortal Wkly Rep. 22 Nov 2016 [Epub ahead of print].
VANCOUVER—Infants infected with Zika virus in utero may develop a syndrome characterized by brain volume loss, intracerebral calcifications, and spasticity. They may develop dyskinesia or seizures after several months, and a subset of children has severe arthrogryposis.
And although microcephaly at birth is common, infants may have a normal head size at birth, but develop postnatal microcephaly or other neurologic symptoms at six months, according to research described at the 45th Annual Meeting of the Child Neurology Society.
“The spectrum of congenital Zika syndrome is expanding as we come to understand it better,” said William B. Dobyns, MD, Professor of Pediatrics at the University of Washington in Seattle and a faculty member at the Center for Integrative Brain Research at Seattle Children’s Research Institute. “We all need to stop calling this microcephaly. This is much more than that. This is the congenital Zika syndrome.”
Zika virus is trophic for neural stem cells, and the first reports of microcephaly associated with prenatal Zika virus infection came from Brazil in January 2016. In the US, mosquitoes that transmit Zika virus, Aedes aegypti and albopictus, are present year round in Florida and seasonally in about a quarter of the states. “It is pretty clear that it will be coming.… We need to take precautions until treatments or preventives are available,” he said. In addition, child neurologists need to be able to recognize congenital Zika syndrome. “It is entirely possible for us to do so,” Dr. Dobyns said. “You do not even need viral titers in the more classically affected children.”
A Case Series of 57 Children
Dr. Dobyns worked with André Pessoa, MD, a child neurologist at Hospital Infantil Albert Sabin in Fortaleza, Brazil, and other neurologists in the region to compile data on a series of 57 children with congenital microcephaly and presumed or proven Zika exposure of the mothers during pregnancy. Microcephaly was defined as occipitofrontal head circumference of at least two standard deviations below the mean.
About half of the children had a bony protuberance of the occipital bone, known as an occipital shelf, Dr. Dobyns said. This feature occurs when the fetal brain, instead of growing and pushing out the skull plates, is severely injured and shrinks. The frontal and parietal bones, but not the occipital bone, collapse over the injured brain.
Almost all of the children had prominent calcifications in the brain. Unlike in children infected with cytomegalovirus, periventricular calcifications are the exception in children infected with Zika virus. Researchers observed subcortical or cortical calcifications on CT in 51 of the 57 children infected with Zika virus and basal ganglia calcifications in 33 of the 57 children.
Furthermore, calcifications with Zika virus infection tend to be diffuse and bilateral, whereas calcifications with cytomegalovirus infection tend to be patchy, Dr. Dobyns said.
All patients had the same general pattern of enlarged extra-axial space, ventriculomegaly, or both, indicating brain volume loss.
About 20% of patients had severe arthrogryposis multiplex congenita, and all of these children had abnormally positioned proximal joints.
Twenty of the children underwent brain MRI. MRI showed an abnormal cortex in all 20 children. The patients appear to have a diffuse cortical malformation that is most consistent with polymicrogyria, Dr. Dobyns said.
Nearly 20% of children in the series had microcephaly between two and three standard deviations below the mean. But 81% had microcephaly of three or more standard deviations below the mean. The mean occipitofrontal head circumference was four standard deviations below the mean.
Neurologic features included spasticity in 94% of the children and severe irritability or tremor in 64% of the children. About 20% had seizures after several months. Some patients had eye abnormalities, including optic nerve pallor, macular atrophy, and strabismus.
“The exam is characteristic,” Dr. Dobyns said. “They all develop a dyskinesia later in the first year of life. They have spastic quadriparesis. They frequently have tremors at birth. They feed poorly. They tend to be irritable and scream all the time. They are starting to have seizures as they get past six months of age.”
As in other studies, data from this series suggest that children whose mothers have a symptomatic illness or are infected earlier in pregnancy may be at higher risk of congenital Zika syndrome.
Infants Without Microcephaly at Birth
Dr. Dobyns presented preliminary data from children who were exposed to Zika virus but did not have microcephaly at birth. These children had most of the same features on exam as children with microcephaly, although the features tended to be less severe. The children started to have seizures after several months. When their head size was measured at six months or older, it fell below the second percentile, meaning that these children had postnatal microcephaly. The children did not have congenital contractures, Dr. Dobyns said.
Vanessa van der Linden, MD, a pediatric neurologist at the Association for Assistance of Disabled Children in Recife, Brazil, Dr. Pessoa, Dr. Dobyns, and colleagues on November 22, 2016, published a description of 13 infants who had evidence of congenital Zika infection but did not have microcephaly at birth. Their report was published online in the CDC’s Morbidity and Mortality Weekly Report. The researchers found that head growth decelerated in all 13 of the infants by as early as age 5 months, and 11 of the infants had microcephaly. The findings suggest that infants exposed to Zika virus prenatally should receive comprehensive medical and developmental follow-up, even in the absence of microcephaly at birth, the investigators said.
That infants with prenatal Zika infection may develop postnatal microcephaly is not surprising, Dr. Dobyns said. Microcephaly, however, remains only one possible symptom of congenital Zika syndrome. “It is a pattern of features seen clinically, on CT scans, and behaviorally that will mark this syndrome,” he said.
—Jake Remaly
Suggested Reading
Moore CA, Staples JE, Dobyns WB, et al. Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians. JAMA Pediatr. 2016 Nov 3 [Epub ahead of print].
van der Linden V, Pessoa A, Dobyns W, et al. Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth — Brazil. MMWR Morb Mortal Wkly Rep. 22 Nov 2016 [Epub ahead of print].
Combined Erythropoietin and Hypothermia May Provide Neuroprotection in Neonates With Hypoxic-Ischemic Encephalopathy
VANCOUVER—Erythropoietin (EPO) plus therapeutic hypothermia may reduce brain injury and improve one-year motor outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), according to phase II trial results presented at the 45th Annual Meeting of the Child Neurology Society.
A large number of in vitro and in vivo studies have shown that EPO has neuroprotective effects after neonatal HIE. “Acutely, it reduces inflammation and apoptosis and improves cell survival. In the long term, it enhances brain repair through a number of mechanisms,” said Yvonne Wu, MD, MPH, Professor of Neurology and Pediatrics at the University of California, San Francisco. 
Hypothermia reduces the risk of death and moderate to severe disability, including cerebral palsy; however, about 40% of infants who are cooled still have adverse outcomes, said Dr. Wu. Studies suggest that multiple doses of EPO provide optimal neuroprotection. In addition, studies in animals have shown that EPO can be neuroprotective even when given up to seven days after the hypoxic-ischemic insult.
To study the effect of EPO and hypothermia combined in neonates with moderate to severe HIE, Dr. Wu and colleagues conducted a randomized, double-blind, placebo-controlled multicenter trial. They evaluated safety, feasibility, and biomarkers of brain injury.
Researchers randomized 50 patients at seven sites to receive either 1,000 U/kg of EPO plus hypothermia or placebo plus hypothermia. Twenty-four babies were randomized to receive EPO and 26 were randomized to receive placebo. Babies received the study drug on five days during the first week of age. Investigators performed MRI on days 4 through 7. They assessed patients’ outcomes at six months and 12 months.
Babies included in the study met standard cooling criteria, including evidence of perinatal distress (eg, Apgar score of less than 5 at 10 minutes). Investigators excluded babies with a genetic disorder, congenital malformation, birth weight less than 1,800 g, microcephaly, or no indwelling line, as well as babies for whom withdrawal of care was considered or who were unlikely to be followed up at 12 months.
To assess neurodevelopmental outcomes at 12 months, researchers administered the Warner Initial Developmental Evaluation (WIDEA), a parental questionnaire that assesses four domains of infant development. In addition, they rated motor function using the Alberta Infant Motor Scale (AIMS). At 12 months, the EPOgroup had a significantly higher AIMS score and a trend toward improvement on the WIDEA score, compared with the placebo group.
Out of 24 infants receiving EPO, 23 had MRI and received three or more doses of treatment. About half of the babies received four to five doses of EPO prior to the MRI.
Researchers scored eight regions of the brain based on the extent of abnormal signal intensity. They found that the babies in the EPO-treated group had a lower median global injury score than those in the placebo group (2 vs 11). In addition, the number of patients with moderate or severe brain MRI abnormalities was lower in the EPO group (one out of 24) versus the placebo group (11 out of 26).
Researchers also noted that EPO appeared to protect the subcortical region of the brain; fewer babies in the EPO-treated group had injury to the deep gray nuclei, compared with babies who received placebo. Two babies died before hospital discharge in the EPO plus hypothermia group, and five died in the hypothermia-alone group. One baby in each group was lost to follow-up at 12 months. No adverse events were considered related to EPO treatment.
“These are small numbers, but our findings raise the possibility that EPO is really doing what we see in animals, which is reducing injury and enhancing repair, so that outcomes are better than expected hypoxic-ischemic encephalopathy,” said Dr. Wu.
—Erica Tricarico
Suggested Reading
Rogers EE, Bonifacio Sl, Glass HC, et al. Erythropoieten and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol. 2014 Aug 24 [Epub ahead of print].
Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Sep 24 [Epub ahead of print].
Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6).
VANCOUVER—Erythropoietin (EPO) plus therapeutic hypothermia may reduce brain injury and improve one-year motor outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), according to phase II trial results presented at the 45th Annual Meeting of the Child Neurology Society.
A large number of in vitro and in vivo studies have shown that EPO has neuroprotective effects after neonatal HIE. “Acutely, it reduces inflammation and apoptosis and improves cell survival. In the long term, it enhances brain repair through a number of mechanisms,” said Yvonne Wu, MD, MPH, Professor of Neurology and Pediatrics at the University of California, San Francisco.
Hypothermia reduces the risk of death and moderate to severe disability, including cerebral palsy; however, about 40% of infants who are cooled still have adverse outcomes, said Dr. Wu. Studies suggest that multiple doses of EPO provide optimal neuroprotection. In addition, studies in animals have shown that EPO can be neuroprotective even when given up to seven days after the hypoxic-ischemic insult.
To study the effect of EPO and hypothermia combined in neonates with moderate to severe HIE, Dr. Wu and colleagues conducted a randomized, double-blind, placebo-controlled multicenter trial. They evaluated safety, feasibility, and biomarkers of brain injury.
Researchers randomized 50 patients at seven sites to receive either 1,000 U/kg of EPO plus hypothermia or placebo plus hypothermia. Twenty-four babies were randomized to receive EPO and 26 were randomized to receive placebo. Babies received the study drug on five days during the first week of age. Investigators performed MRI on days 4 through 7. They assessed patients’ outcomes at six months and 12 months.
Babies included in the study met standard cooling criteria, including evidence of perinatal distress (eg, Apgar score of less than 5 at 10 minutes). Investigators excluded babies with a genetic disorder, congenital malformation, birth weight less than 1,800 g, microcephaly, or no indwelling line, as well as babies for whom withdrawal of care was considered or who were unlikely to be followed up at 12 months.
To assess neurodevelopmental outcomes at 12 months, researchers administered the Warner Initial Developmental Evaluation (WIDEA), a parental questionnaire that assesses four domains of infant development. In addition, they rated motor function using the Alberta Infant Motor Scale (AIMS). At 12 months, the EPOgroup had a significantly higher AIMS score and a trend toward improvement on the WIDEA score, compared with the placebo group.
Out of 24 infants receiving EPO, 23 had MRI and received three or more doses of treatment. About half of the babies received four to five doses of EPO prior to the MRI.
Researchers scored eight regions of the brain based on the extent of abnormal signal intensity. They found that the babies in the EPO-treated group had a lower median global injury score than those in the placebo group (2 vs 11). In addition, the number of patients with moderate or severe brain MRI abnormalities was lower in the EPO group (one out of 24) versus the placebo group (11 out of 26).
Researchers also noted that EPO appeared to protect the subcortical region of the brain; fewer babies in the EPO-treated group had injury to the deep gray nuclei, compared with babies who received placebo. Two babies died before hospital discharge in the EPO plus hypothermia group, and five died in the hypothermia-alone group. One baby in each group was lost to follow-up at 12 months. No adverse events were considered related to EPO treatment.
“These are small numbers, but our findings raise the possibility that EPO is really doing what we see in animals, which is reducing injury and enhancing repair, so that outcomes are better than expected hypoxic-ischemic encephalopathy,” said Dr. Wu.
—Erica Tricarico
Suggested Reading
Rogers EE, Bonifacio Sl, Glass HC, et al. Erythropoieten and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol. 2014 Aug 24 [Epub ahead of print].
Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Sep 24 [Epub ahead of print].
Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6).
VANCOUVER—Erythropoietin (EPO) plus therapeutic hypothermia may reduce brain injury and improve one-year motor outcomes in neonates with hypoxic-ischemic encephalopathy (HIE), according to phase II trial results presented at the 45th Annual Meeting of the Child Neurology Society.
A large number of in vitro and in vivo studies have shown that EPO has neuroprotective effects after neonatal HIE. “Acutely, it reduces inflammation and apoptosis and improves cell survival. In the long term, it enhances brain repair through a number of mechanisms,” said Yvonne Wu, MD, MPH, Professor of Neurology and Pediatrics at the University of California, San Francisco.
Hypothermia reduces the risk of death and moderate to severe disability, including cerebral palsy; however, about 40% of infants who are cooled still have adverse outcomes, said Dr. Wu. Studies suggest that multiple doses of EPO provide optimal neuroprotection. In addition, studies in animals have shown that EPO can be neuroprotective even when given up to seven days after the hypoxic-ischemic insult.
To study the effect of EPO and hypothermia combined in neonates with moderate to severe HIE, Dr. Wu and colleagues conducted a randomized, double-blind, placebo-controlled multicenter trial. They evaluated safety, feasibility, and biomarkers of brain injury.
Researchers randomized 50 patients at seven sites to receive either 1,000 U/kg of EPO plus hypothermia or placebo plus hypothermia. Twenty-four babies were randomized to receive EPO and 26 were randomized to receive placebo. Babies received the study drug on five days during the first week of age. Investigators performed MRI on days 4 through 7. They assessed patients’ outcomes at six months and 12 months.
Babies included in the study met standard cooling criteria, including evidence of perinatal distress (eg, Apgar score of less than 5 at 10 minutes). Investigators excluded babies with a genetic disorder, congenital malformation, birth weight less than 1,800 g, microcephaly, or no indwelling line, as well as babies for whom withdrawal of care was considered or who were unlikely to be followed up at 12 months.
To assess neurodevelopmental outcomes at 12 months, researchers administered the Warner Initial Developmental Evaluation (WIDEA), a parental questionnaire that assesses four domains of infant development. In addition, they rated motor function using the Alberta Infant Motor Scale (AIMS). At 12 months, the EPOgroup had a significantly higher AIMS score and a trend toward improvement on the WIDEA score, compared with the placebo group.
Out of 24 infants receiving EPO, 23 had MRI and received three or more doses of treatment. About half of the babies received four to five doses of EPO prior to the MRI.
Researchers scored eight regions of the brain based on the extent of abnormal signal intensity. They found that the babies in the EPO-treated group had a lower median global injury score than those in the placebo group (2 vs 11). In addition, the number of patients with moderate or severe brain MRI abnormalities was lower in the EPO group (one out of 24) versus the placebo group (11 out of 26).
Researchers also noted that EPO appeared to protect the subcortical region of the brain; fewer babies in the EPO-treated group had injury to the deep gray nuclei, compared with babies who received placebo. Two babies died before hospital discharge in the EPO plus hypothermia group, and five died in the hypothermia-alone group. One baby in each group was lost to follow-up at 12 months. No adverse events were considered related to EPO treatment.
“These are small numbers, but our findings raise the possibility that EPO is really doing what we see in animals, which is reducing injury and enhancing repair, so that outcomes are better than expected hypoxic-ischemic encephalopathy,” said Dr. Wu.
—Erica Tricarico
Suggested Reading
Rogers EE, Bonifacio Sl, Glass HC, et al. Erythropoieten and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol. 2014 Aug 24 [Epub ahead of print].
Wu YW, Bauer LA, Ballard RA, et al. Erythropoietin for neuroprotection in neonatal encephalopathy: safety and pharmacokinetics. Pediatrics. 2012 Sep 24 [Epub ahead of print].
Wu YW, Mathur AM, Chang T, et al. High-dose erythropoietin and hypothermia for hypoxic-ischemic encephalopathy: a phase II trial. Pediatrics. 2016;137(6).
