- Email: [email protected]
Short Takes
Pediatric Neurology xxx (2017) 1e2
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Commentary
Short Takes Steven G. Pavlakis MD * Department of Pediatrics and Icahn School of Medicine at Mount Sinai, The Brooklyn Hospital, Brooklyn, NewYork
“Betsy DeVos Invests in Therapy Under Scrutiny.” New York Times. January 30, 2017 Fink S, Eder S, Goldstein M. Flash summary: Betsy DeVos, the Secretary of Education, is financially backing a group of centers called Neurocore. The company reports improvement in 90% of individuals with attention-deficit/hyperactivity disorder (ADHD) as well as other conditions including anxiety, migraine, and depression, which also show greater than 80% effect size with treatment. Furthermore, Neurocore claims that it delivers improved cognition using neurofeedback and improves ADHD symptoms. The company has eight centers in the United States. Based on the company’s web site, the program attempts to retrain the distractible brain using videos and electrophysiologic brain mapping in a neurofeedback model. The web site states “neurofeedback and biofeedback sessions takes advantage of your brain’s ability to change-that’s neuroplasticity.” The web site further claims that the program results in improved focus and attention. Neurocore’s Chief Medical Officer states “there is significant research to support the efficacy of neurofeedback for a variety of mental and behavioral issues.” According to this New York Times article, treatment is supervised by students or social workers. Bottom line: Whether Ms. DeVos gets to keep her financial interest in Neurocore as Secretary of Education is not the question for pediatric neurologists. Here there are political and legal issues, but these are not under our purview. What we as neurologists are charged with is to keep medical interventions transparent and honest. Neurocore’s Chief Medical Officer stated that there is “significant” research for neurofeedback. In medicine, significant should only mean statistically meaningful. In other words, it should be a statistical term and not a term of hyperbole. Here there are no such data of statistical improvement for neurofeedback and ADHD treatment compared with a control group. Indeed, the web site has a link to a 1998 article that shows an increased intelligence quotient after neurofeedback, but this was not a prospective study with
Editor’s note: Short Takes offers a brief analysis by Steven G. Pavlakis of selected articles that may be of interest to child neurologists. Papers that strike the fancy of the analyst or the editors are selected for inclusion, but we welcome suggestions. * Communications should be addressed to: Dr. Pavlakis; Department of Pediatrics and Icahn School of Medicine at Mount Sinai; The Brooklyn Hospital; 121 DeKalb Ave; Brooklyn, NY 11201. E-mail address: [email protected] 0887-8994/$ e see front matter http://dx.doi.org/10.1016/j.pediatrneurol.2017.06.002
control groups. The 1998 article suggests that further studies need to be done. So for almost 20 years there is still no statistically sound research on these methodologies. Still the methodology is used to target neuroplasticity directly. There are no data whatsoever proving that neuroplasticity is the mechanism of action for neurofeedback. Neuroplasticity is also a term that can be defined and tested, and here it is not. We should be at the forefront of tempering claims for efficacy in the diseases that we treat until studies are performed showing efficacy. Before phase 3 trials, providers as well as companies offering a product should not claim near-unequivocal effect. We neurologists could also serve to help perform real studies so that we feel comfortable with any treatments. It would be wonderful if we can prove that neurofeedback improves ADHD and has lasting efficacy. That would be a real benefit for our patients. Pediatric neurologists could even offer our services pro bono publico for trial design to companies such as Neurocore, so that we can help define the standard of care. The study here would need to be double blind with a sham control group. It can be easily done, and the only impediments are a willingness and the cost.
2
Short Takes / Pediatric Neurology xxx (2017) 1e2
Parental rheumatoid arthritis and childhood epilepsy. Neurology 2016;87:2510-2516
Neonatal vitamin D status and risk of multiple sclerosis: A population-based case-control study. Neurology 2017;88:44-51
Rom AL, Wu CS, Olsen J, et al.
Nielsen NM, Munger KL, Koch-Henriksen N, et al.
Flash summary: This was a nationwide Danish study of singleton births from 1977 to 2008 (n ¼ 1,917,723). The birth data were linked to a clinical registry. Children (n ¼ 13,511) exposed to maternal rheumatoid arthritis (RA) during the perinatal period were analyzed. The outcome measure was the development of clinical epilepsy in children born of mothers who had either clinical or preclinical RA during pregnancy. The children were followed for 16 years on an average. The outcome of epilepsy was stratified by the age of onset as follows: early epilepsy 30 days to four years, late childhood six to 15 years, and adolescent epilepsy greater than age 15 years.
Flash summary: This is a matched case-control study. Dried neonatal blood spots belonging to 521 patients (up to age 30 years) with multiple sclerosis (MS) were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1 to 2 age-matched control subjects were analyzed (n ¼ 972). Newborn levels of 25-hydroxyvitamin D (25(OH)D) were measured by liquid chromatography-mass spectroscopy on stored newborn samples. The levels of 25(OH)D and risk of MS were assessed using odds ratios. The authors found that lower levels of 25(OH)D were associated with an increased risk of MS. MS risk was highest in patients in the bottom newborn 25(OH)D level quintile and lowest among those in the top quintile. Looking at 25(OH)D concentrations as a continuous variable, the incidence of MS increased with a 25 nmol/L increase in neonatal 25(OH)D concentration, resulting in a 30% increase in MS risk.
Children exposed to maternal RA had an increased risk of early and late childhood epilepsies, whereas children exposed to maternal RA had no increased risk of adolescent or adulthood epilepsy. Paternal RA was not associated with an increased risk of epilepsy. The authors conclude that in utero exposure to RA increases the risk of epilepsy in children. Specifically, the study suggests a 90% increased risk of early childhood epilepsy in children of mothers with RA and a 30% increased risk in children whose mothers had preclinical RA during gestation. Late childhood epilepsy risk was increased 30% in children born of mothers with either preclinical or clinical RA. Bottom line: In an accompanying editorial, it is stated that there is evidence that maternal autoimmune disease influences the development of the neonatal brain. Associations have been made with Tourette syndrome as well as autism. Here epilepsy is associated with maternal RA but not paternal RA. As such, this suggests that the fetal milieu is the culprit, but it neither excludes genetic influences nor definitively excludes maternal medications. The only way to proceed in determining the pathophysiology would be a clinical investigation of the children with epilepsy born of mothers with RA. These children need to be compared with children with early epilepsy born of healthy mothers. Epidemiology goes only so far; now clinical investigations are warranted to better elucidate the potential mechanism for this association. Having said this, neurological complications of autoimmune disease are complex and not well understood. For example, the complex nature of systemic lupus encephalopathy, associated seizures, and acute neurological deteriorations are, in my opinion, often not well defined. Here we need to try to understand the effect of autoimmune disease on the fetal brain. This is potentially even more complicated. Nevertheless, a clinical study defining these children is the next step to a better understanding.
Bottom line: The authors conclude that low concentrations of neonatal vitamin D are associated with the later onset of MS. Nielson and coauthors opine that because of the high risk of low vitamin D in the population, especially in the northern hemisphere, this observation might have important public health implications. In the accompanying editorial, the weaknesses of the article are outlined, including the fact that neonatal blood was not available in 22% of MS cases, the vitamin D levels obtained may not reflect concentrations throughout the perinatal period, and the diagnosis of MS was confirmed by age 30 years, therefore patients with older age of MS onset would be missed. In addition, smoking and obesity, which are known risk factors for the development of MS, were not assessed. The concept that perinatal environmental conditions are potential risk factors for later onset and adult diseases could be game changing. The potential public health interventions, in this case, are obvious. It is difficult to prove this association, and treatment trials with vitamin D are complicated by the number of patients needed to treat and the long observation periods required to prove a treatment effect. Nevertheless, this type of study is interesting and with time may help us piece together the puzzle of early fetal and postnatal conditions that may result in later onset diseases.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Commentary
Short Takes Steven G. Pavlakis MD * Department of Pediatrics and Icahn School of Medicine at Mount Sinai, The Brooklyn Hospital, Brooklyn, NewYork
“Betsy DeVos Invests in Therapy Under Scrutiny.” New York Times. January 30, 2017 Fink S, Eder S, Goldstein M. Flash summary: Betsy DeVos, the Secretary of Education, is financially backing a group of centers called Neurocore. The company reports improvement in 90% of individuals with attention-deficit/hyperactivity disorder (ADHD) as well as other conditions including anxiety, migraine, and depression, which also show greater than 80% effect size with treatment. Furthermore, Neurocore claims that it delivers improved cognition using neurofeedback and improves ADHD symptoms. The company has eight centers in the United States. Based on the company’s web site, the program attempts to retrain the distractible brain using videos and electrophysiologic brain mapping in a neurofeedback model. The web site states “neurofeedback and biofeedback sessions takes advantage of your brain’s ability to change-that’s neuroplasticity.” The web site further claims that the program results in improved focus and attention. Neurocore’s Chief Medical Officer states “there is significant research to support the efficacy of neurofeedback for a variety of mental and behavioral issues.” According to this New York Times article, treatment is supervised by students or social workers. Bottom line: Whether Ms. DeVos gets to keep her financial interest in Neurocore as Secretary of Education is not the question for pediatric neurologists. Here there are political and legal issues, but these are not under our purview. What we as neurologists are charged with is to keep medical interventions transparent and honest. Neurocore’s Chief Medical Officer stated that there is “significant” research for neurofeedback. In medicine, significant should only mean statistically meaningful. In other words, it should be a statistical term and not a term of hyperbole. Here there are no such data of statistical improvement for neurofeedback and ADHD treatment compared with a control group. Indeed, the web site has a link to a 1998 article that shows an increased intelligence quotient after neurofeedback, but this was not a prospective study with
Editor’s note: Short Takes offers a brief analysis by Steven G. Pavlakis of selected articles that may be of interest to child neurologists. Papers that strike the fancy of the analyst or the editors are selected for inclusion, but we welcome suggestions. * Communications should be addressed to: Dr. Pavlakis; Department of Pediatrics and Icahn School of Medicine at Mount Sinai; The Brooklyn Hospital; 121 DeKalb Ave; Brooklyn, NY 11201. E-mail address: [email protected] 0887-8994/$ e see front matter http://dx.doi.org/10.1016/j.pediatrneurol.2017.06.002
control groups. The 1998 article suggests that further studies need to be done. So for almost 20 years there is still no statistically sound research on these methodologies. Still the methodology is used to target neuroplasticity directly. There are no data whatsoever proving that neuroplasticity is the mechanism of action for neurofeedback. Neuroplasticity is also a term that can be defined and tested, and here it is not. We should be at the forefront of tempering claims for efficacy in the diseases that we treat until studies are performed showing efficacy. Before phase 3 trials, providers as well as companies offering a product should not claim near-unequivocal effect. We neurologists could also serve to help perform real studies so that we feel comfortable with any treatments. It would be wonderful if we can prove that neurofeedback improves ADHD and has lasting efficacy. That would be a real benefit for our patients. Pediatric neurologists could even offer our services pro bono publico for trial design to companies such as Neurocore, so that we can help define the standard of care. The study here would need to be double blind with a sham control group. It can be easily done, and the only impediments are a willingness and the cost.
2
Short Takes / Pediatric Neurology xxx (2017) 1e2
Parental rheumatoid arthritis and childhood epilepsy. Neurology 2016;87:2510-2516
Neonatal vitamin D status and risk of multiple sclerosis: A population-based case-control study. Neurology 2017;88:44-51
Rom AL, Wu CS, Olsen J, et al.
Nielsen NM, Munger KL, Koch-Henriksen N, et al.
Flash summary: This was a nationwide Danish study of singleton births from 1977 to 2008 (n ¼ 1,917,723). The birth data were linked to a clinical registry. Children (n ¼ 13,511) exposed to maternal rheumatoid arthritis (RA) during the perinatal period were analyzed. The outcome measure was the development of clinical epilepsy in children born of mothers who had either clinical or preclinical RA during pregnancy. The children were followed for 16 years on an average. The outcome of epilepsy was stratified by the age of onset as follows: early epilepsy 30 days to four years, late childhood six to 15 years, and adolescent epilepsy greater than age 15 years.
Flash summary: This is a matched case-control study. Dried neonatal blood spots belonging to 521 patients (up to age 30 years) with multiple sclerosis (MS) were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1 to 2 age-matched control subjects were analyzed (n ¼ 972). Newborn levels of 25-hydroxyvitamin D (25(OH)D) were measured by liquid chromatography-mass spectroscopy on stored newborn samples. The levels of 25(OH)D and risk of MS were assessed using odds ratios. The authors found that lower levels of 25(OH)D were associated with an increased risk of MS. MS risk was highest in patients in the bottom newborn 25(OH)D level quintile and lowest among those in the top quintile. Looking at 25(OH)D concentrations as a continuous variable, the incidence of MS increased with a 25 nmol/L increase in neonatal 25(OH)D concentration, resulting in a 30% increase in MS risk.
Children exposed to maternal RA had an increased risk of early and late childhood epilepsies, whereas children exposed to maternal RA had no increased risk of adolescent or adulthood epilepsy. Paternal RA was not associated with an increased risk of epilepsy. The authors conclude that in utero exposure to RA increases the risk of epilepsy in children. Specifically, the study suggests a 90% increased risk of early childhood epilepsy in children of mothers with RA and a 30% increased risk in children whose mothers had preclinical RA during gestation. Late childhood epilepsy risk was increased 30% in children born of mothers with either preclinical or clinical RA. Bottom line: In an accompanying editorial, it is stated that there is evidence that maternal autoimmune disease influences the development of the neonatal brain. Associations have been made with Tourette syndrome as well as autism. Here epilepsy is associated with maternal RA but not paternal RA. As such, this suggests that the fetal milieu is the culprit, but it neither excludes genetic influences nor definitively excludes maternal medications. The only way to proceed in determining the pathophysiology would be a clinical investigation of the children with epilepsy born of mothers with RA. These children need to be compared with children with early epilepsy born of healthy mothers. Epidemiology goes only so far; now clinical investigations are warranted to better elucidate the potential mechanism for this association. Having said this, neurological complications of autoimmune disease are complex and not well understood. For example, the complex nature of systemic lupus encephalopathy, associated seizures, and acute neurological deteriorations are, in my opinion, often not well defined. Here we need to try to understand the effect of autoimmune disease on the fetal brain. This is potentially even more complicated. Nevertheless, a clinical study defining these children is the next step to a better understanding.
Bottom line: The authors conclude that low concentrations of neonatal vitamin D are associated with the later onset of MS. Nielson and coauthors opine that because of the high risk of low vitamin D in the population, especially in the northern hemisphere, this observation might have important public health implications. In the accompanying editorial, the weaknesses of the article are outlined, including the fact that neonatal blood was not available in 22% of MS cases, the vitamin D levels obtained may not reflect concentrations throughout the perinatal period, and the diagnosis of MS was confirmed by age 30 years, therefore patients with older age of MS onset would be missed. In addition, smoking and obesity, which are known risk factors for the development of MS, were not assessed. The concept that perinatal environmental conditions are potential risk factors for later onset and adult diseases could be game changing. The potential public health interventions, in this case, are obvious. It is difficult to prove this association, and treatment trials with vitamin D are complicated by the number of patients needed to treat and the long observation periods required to prove a treatment effect. Nevertheless, this type of study is interesting and with time may help us piece together the puzzle of early fetal and postnatal conditions that may result in later onset diseases.