Publications by authors named "Deborah Hirtz"

77 Publications

Practice guideline: Treatment for insomnia and disrupted sleep behavior in children and adolescents with autism spectrum disorder: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

Neurology 2020 03 12;94(9):392-404. Epub 2020 Feb 12.

From the Pediatrics and Developmental Neuroscience Branch (A.W.B., T.G., R.K., A.T.), National Institute of Mental Health, NIH, Bethesda, MD; Department of Neurological Sciences (D.H.), University of Vermont Medical Center, Burlington; Department of Pediatric Neurology (M.O.), McGill University Health Centre, Montréal, Canada; Department of Neurology (M.J.A.), University of Florida College of Medicine, Gainesville; Developmental Pediatrics (A.B.), Our Special Kids Pediatric Care, Los Angeles, CA; Division of Developmental Medicine (C.B.) and Center for Pediatric Sleep Disorders (J.O.), Boston Children's Hospital, MA; Departments of Pediatrics and Psychiatry (D.C.), The Ohio State University College of Medicine, Columbus; Duke Center for Autism and Brain Development (G.D., L.S.), Duke University School of Medicine, Durham, NC; Northern Michigan Neurology (D.D.), Traverse City; Department of Child and Behavioral Sciences (R.L.F.), Johns Hopkins University, Baltimore, MD; Department of Neurology (D.G.), Charleston Area Medical Center, WV; Department of Neurology (G.G.), Kansas University Medical Center, Kansas City; American Academy of Neurology (S.M.), Minneapolis, MN; Division of Pediatric Neurology, Department of Pediatrics (D.M., S.A.), Loma Linda University School of Medicine, CA; Department of Clinical Neurosciences (T.P.), University of Calgary, Alberta, Canada; Department of Psychiatry and Behavioral Science and MIND Institute (A.S.), University of California, Davis; Division of Neurology (R.T.), Nicklaus Children's Hospital and Miami Children's Hospital, FL; Treatment and Research Institute for Autism Spectrum Disorders (Z.W.), Vanderbilt Kennedy Center, Nashville, TN; Autism Institute, College of Medicine (A.W.), Florida State University, Tallahassee; and Division of Neurology (M.W.), Rainbow Babies & Children's Hospital, Cleveland, OH.

Objective: To review pharmacologic and nonpharmacologic strategies for treating sleep disturbances in children and adolescents with autism spectrum disorder (ASD) and to develop recommendations for addressing sleep disturbance in this population.

Methods: The guideline panel followed the American Academy of Neurology 2011 guideline development process, as amended. The systematic review included studies through December 2017. Recommendations were based on evidence, related evidence, principles of care, and inferences.

Major Recommendations Level B: For children and adolescents with ASD and sleep disturbance, clinicians should assess for medications and coexisting conditions that could contribute to the sleep disturbance and should address identified issues. Clinicians should counsel parents regarding strategies for improved sleep habits with behavioral strategies as a first-line treatment approach for sleep disturbance either alone or in combination with pharmacologic or nutraceutical approaches. Clinicians should offer melatonin if behavioral strategies have not been helpful and contributing coexisting conditions and use of concomitant medications have been addressed, starting with a low dose. Clinicians should recommend using pharmaceutical-grade melatonin if available. Clinicians should counsel children, adolescents, and parents regarding potential adverse effects of melatonin use and the lack of long-term safety data. Clinicians should counsel that there is currently no evidence to support the routine use of weighted blankets or specialized mattress technology for improving disrupted sleep. If asked about weighted blankets, clinicians should counsel that the trial reported no serious adverse events with blanket use and that blankets could be a reasonable nonpharmacologic approach for some individuals.
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http://dx.doi.org/10.1212/WNL.0000000000009033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238942PMC
March 2020

Sensitivity and specificity of early screening for autism.

BJPsych Open 2019 May 17;5(3):e41. Epub 2019 May 17.

Director General and Professor, Norwegian Institute of Public Health; and Department of Global Public Health and Primary Care, University of Bergen, Norway.

Background: Early identification and diagnosis is beneficial for children with autism spectrum disorder (ASD). Universal early screening is recommended by many experts, but disputed because evidence is limited, and sensitivity and specificity in general populations are largely unknown.

Aims: To estimate the sensitivity and specificity of early population-based screening for ASDs.

Method: The study was based on the Norwegian Mother and Child Cohort Study. The 36-month cohort questionnaire included the Social Communication Questionnaire (SCQ), a 40-item screening instrument for ASD.

Results: A total of 58 520 mothers (58%) responded to the questionnaire. By the end of follow-up on 31 December 2015, 385 (0.7%) individuals with ASD had been identified among the responders' children. The distributions of SCQ scores in those with ASD and other children had large degrees of overlap. With the cut-off of 15 recommended in the SCQ manual, screening sensitivity was 20% (95% CI 16-24) for ASD overall. For children with ASD who had not developed phrase speech at 36 months, sensitivity was 46% (95% CI 35-57%), whereas it was 13% (95% CI 9-17) for children with ASD with phrase speech. Screening specificity was 99% (95% CI 99-99). With the currently recommended cut-off of 11, sensitivity increased to 42% for ASD overall (95% CI 37-47), 69% (95% CI 58-79) for ASD without phrase speech and 34% (95% CI 29-40) for ASD with phrase speech. Specificity was then reduced to 89% (95% CI 89-90).

Conclusions: Early ASD screening with a parent checklist had low sensitivity. It identified mainly individuals with ASD with significant developmental delay and captured very few children with ASD with cognitive skills in the normal range. Increasing sensitivity was not possible without severely compromising specificity.

Declaration Of Interest: C.L. receives royalty for the Social Communication Questionnaire, which she has co-authored.
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http://dx.doi.org/10.1192/bjo.2019.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537444PMC
May 2019

Association of Circulating Proinflammatory and Anti-inflammatory Protein Biomarkers in Extremely Preterm Born Children with Subsequent Brain Magnetic Resonance Imaging Volumes and Cognitive Function at Age 10 Years.

J Pediatr 2019 07 7;210:81-90.e3. Epub 2019 May 7.

Department of Epidemiology and Biostatistics and Pediatrics, Michigan State University, East Lansing, MI.

Objectives: To examine elevated neonatal inflammatory and neurotrophic proteins from children born extremely preterm in relation to later childhood brain Magnetic Resonance Imaging volumes and cognition.

Study Design: We measured circulating inflammation-related proteins and neurotrophic proteins on postnatal days 1, 7, and 14 in 166 children at 10 years of age (73 males; 93 females). Top quartile levels on ≥2 days for ≥3 inflammation-related proteins and for ≥4 neurotrophic proteins defined exposure. We examined associations among protein levels, brain Magnetic Resonance Imaging volumes, and cognition with multiple linear and logistic regressions.

Results: Analyses were adjusted for gestational age at birth and sex. Children with ≥3 elevated inflammation-related proteins had smaller grey matter, brain stem/cerebellar, and total brain volumes than those without elevated inflammation-related proteins, adjusted for neurotrophic proteins. When adjusted for inflammation-related proteins, children with ≥4 neurotrophic proteins, compared with children with no neurotrophic proteins, had larger grey matter and total brain volumes. Higher grey matter, white matter, and cerebellum and brainstem volumes were significantly correlated with higher IQ. Grey and white matter volumes were correlated with each other (r = -0.18; P = .021), and cerebellum and brainstem was highly correlated with grey matter (r = 0.55; P < .001) and white matter (r = 0.29; P < .001). Adjusting for other brain compartments, cerebellum and brainstem was associated with IQ (P = .016), but the association with white matter was marginally significant (P = .051). Grey matter was not associated with IQ. After adjusting for brain volumes, elevated inflammation-related proteins remained significantly associated with a lower IQ, and elevated neurotrophic proteins remained associated with a higher IQ.

Conclusions: Newborn inflammatory and neurotrophin protein levels are associated with later brain volumes and cognition, but their effects on cognition are not entirely explained by altered brain volumes.
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http://dx.doi.org/10.1016/j.jpeds.2019.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137312PMC
July 2019

Sickle Cell Disease and Stroke.

Pediatr Neurol 2019 06 27;95:34-41. Epub 2019 Feb 27.

Developmental Neurosciences Section and Biomedical Research Unit, Clinical and Experimental Sciences, University of Southampton, UCL Great Ormond Street Institute of Child Health, London, UK. Electronic address:

Cerebral infarction is a common complication of sickle cell disease and may manifest as overt stroke or cognitive impairment associated with "silent" cerebral infarction on magnetic resonance imaging. Vasculopathy may be diagnosed on transcranial Doppler or magnetic resonance angiography. The risk factors in sickle cell disease for cognitive impairment, overt ischemic stroke, silent cerebral infarction, overt hemorrhagic stroke, and vasculopathy defined by transcranial Doppler or magnetic resonance angiography overlap, with severe acute and chronic anemia, acute chest crisis, reticulocytosis, and low oxygen saturation reported with the majority. However, there are differences reported in different cohorts, which may reflect age, geographic location, or neuroimaging techniques, for example, magnetic resonance imaging field strength. Regular blood transfusion reduces, but does not abolish, the risk of neurological complications in children with sickle cell disease and either previous overt stroke or silent cerebral infarction or abnormal transcranial Doppler. There are relatively few data on the use of hydroxyurea or other management strategies. Early assessment of the risk of neurocognitive complications is likely to become increasingly important in the management of sickle cell disease.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.02.018DOI Listing
June 2019

Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy: Report of the American Epilepsy Society and the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

Epilepsy Curr 2018 Jul-Aug;18(4):269-278

15New York University, New York City, NY.

To update the 2004 American Academy of Neurology (AAN) guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs). 2004 criteria were used to systematically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Forty-two articles were included. The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment; rufinamide for Lennox-Gastuat syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic-clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month to 16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6-17 years); oxcarbazepine for TRCFE (1 month to 4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidence-based assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent FDA strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years of age and perampanel as monotherapy received FDA approval.
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http://dx.doi.org/10.5698/1535-7597.18.4.269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145395PMC
September 2018

Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the American Epilepsy Society and the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

Epilepsy Curr 2018 Jul-Aug;18(4):260-268

15Department of Neurology, New York University Langone Comprehensive Epilepsy Center, New York.

To update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy (GE) with second- and third-generation antiepileptic drugs (AEDs). The 2004 AAN criteria was used to systematically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Several second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic-clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy. Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years with new-onset focal epilepsy. Unless there are compelling adverse-effect-related concerns, ethosuximide (ETS) or valproic acid (VPA) should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (Level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent FDA strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.
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http://dx.doi.org/10.5698/1535-7597.18.4.260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6145382PMC
September 2018

Among Children Born Extremely Preterm a Higher Level of Circulating Neurotrophins Is Associated with Lower Risk of Cognitive Impairment at School Age.

J Pediatr 2018 10 18;201:40-48.e4. Epub 2018 Jul 18.

Department of Epidemiology and Biostatistics and Pediatrics & Human Development, Michigan State University, East Lansing, MI.

Objectives: To test the hypothesis that higher blood levels of neurotrophic proteins (proteins that support neuronal survival and function) in the first 2 weeks of life are associated with a lower risk of cognitive impairment at 10 years.

Study Design: We evaluated 812 10-year-old children with neonatal blood specimens enrolled in the multicenter prospective Extremely Low Gestational Age Newborn Study, assessing 22 blood proteins collected on 3 days over the first 2 weeks of life. Using latent profile analysis, we derived a cognitive function level based on standardized cognitive and executive function tests. We defined high exposure as the top quartile neurotrophic protein blood level on ≥2 days either for ≥4 proteins or for a specific cluster of neurotrophic proteins (defined by latent class analysis). Multinomial logistic regression analyzed associations between high exposures and cognitive impairment.

Results: Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18-0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09-0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain-derived neurotrophic factor, and regulated upon activation, normal T-cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31-0.6). The risk for moderate to severe cognitive impairment was least with 0-1 inflammatory and >4 neurotrophic proteins.

Conclusions: Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins.
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http://dx.doi.org/10.1016/j.jpeds.2018.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684153PMC
October 2018

Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs II: Treatment-resistant epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

Neurology 2018 07 13;91(2):82-90. Epub 2018 Jun 13.

From Miller School of Medicine (A.M.K.), University of Miami, FL; Bronson Methodist Hospital (E.A.), Kalamazoo, MI; Charleston Area Medical Center (D.G.), Charleston, WV; Mount Sinai Beth Israel (C.H.), New York, NY; Children's Hospital, Harvard Medical School (B.B.), Boston, MA; Cleveland Clinic Foundation (J.F.B.), OH; Department of Neurology (B.-A.K.), School of Medicine, Nashville, TN; Cooper Medical School (E.B.-D.), Rowan University, Cherry Hill, NJ; Alexian Brothers Medical Group (E.L.P.), Hoffman Estates, IL; School of Medicine (J.S.), University of California in Los Angeles; University of Vermont Medical Center (D.H.), Burlington; Children's Hospital (M.N.), University of California San Diego School of Medicine; School of Pharmacy (B.G.), University of Wisconsin, Madison; Emory University School of Medicine (E.F.), Atlanta, GA; and New York University (J.F.), New York.

Objective: To update the 2004 American Academy of Neurology guideline for managing treatment-resistant (TR) epilepsy with second- and third-generation antiepileptic drugs (AEDs).

Methods: 2004 criteria were used to systemically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength.

Results: Forty-two articles were included.

Recommendations: The following are established as effective to reduce seizure frequency (Level A): immediate-release pregabalin and perampanel for TR adult focal epilepsy (TRAFE); vigabatrin for TRAFE (not first-line treatment); rufinamide for Lennox-Gastaut syndrome (LGS) (add-on therapy). The following should be considered to decrease seizure frequency (Level B): lacosamide, eslicarbazepine, and extended-release topiramate for TRAFE (ezogabine production discontinued); immediate- and extended-release lamotrigine for generalized epilepsy with TR generalized tonic-clonic (GTC) seizures in adults; levetiracetam (add-on therapy) for TR childhood focal epilepsy (TRCFE) (1 month-16 years), TR GTC seizures, and TR juvenile myoclonic epilepsy; clobazam for LGS (add-on therapy); zonisamide for TRCFE (6-17 years); oxcarbazepine for TRCFE (1 month-4 years). The text presents Level C recommendations. AED selection depends on seizure/syndrome type, patient age, concomitant medications, and AED tolerability, safety, and efficacy. This evidence-based assessment informs AED prescription guidelines for TR epilepsy and indicates seizure types and syndromes needing more evidence. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years of age and perampanel as monotherapy received FDA approval.
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http://dx.doi.org/10.1212/WNL.0000000000005756DOI Listing
July 2018

Practice guideline update summary: Efficacy and tolerability of the new antiepileptic drugs I: Treatment of new-onset epilepsy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

Neurology 2018 07 13;91(2):74-81. Epub 2018 Jun 13.

From the Miller School of Medicine (A.M.K.), University of Miami, FL; Bronson Neuroscience Center (E.A.), Bronson Methodist Hospital, Kalamazoo, MI; Department of Neurology (D.G.), Charleston Area Medical Center, Charleston, WV; Department of Neurology (C.H.), Mount Sinai Beth Israel, New York, NY; Children's Hospital (B.B.), Harvard Medical School, Boston, MA; Epilepsy Center (J.F.B.), Cleveland Clinic Foundation, OH; Department of Neurology (B.A.-K.), Vanderbilt University, Nashville, TN; Department of Neurology (E.B.-D.), Cooper Medical School, Rowan University, Cherry Hill, NJ; AMITA Health Medical Group (E.L.P.), Hoffman Estates, IL; School of Medicine (J.S.), University of California, Los Angeles; School of Medicine (D.H.), University of Vermont, Burlington; Children's Hospital (M.N.), University of California San Diego School of Medicine; School of Pharmacy (B.G.), University of Wisconsin, Madison; School of Medicine (E.F.), Emory University, Atlanta, GA; and Department of Neurology (J.F.), New York University Langone Comprehensive Epilepsy Center, New York.

Objective: To update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy with second- and third-generation antiepileptic drugs (AEDs).

Methods: The 2004 AAN criteria were used to systematically review literature (January 2003-November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength.

Results: Several second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic-clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy.

Recommendations: Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years of age with new-onset focal epilepsy. Unless there are compelling adverse effect-related concerns, ethosuximide or valproic acid should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent Food and Drug Administration (FDA) strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.
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http://dx.doi.org/10.1212/WNL.0000000000005755DOI Listing
July 2018

A checklist for clinical trials in rare disease: obstacles and anticipatory actions-lessons learned from the FOR-DMD trial.

Trials 2018 May 10;19(1):291. Epub 2018 May 10.

John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.

Background: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013.

Method: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies.

Results: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients.

Conclusion: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.
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http://dx.doi.org/10.1186/s13063-018-2645-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968578PMC
May 2018

Co-occurrence and Severity of Neurodevelopmental Burden (Cognitive Impairment, Cerebral Palsy, Autism Spectrum Disorder, and Epilepsy) at Age Ten Years in Children Born Extremely Preterm.

Pediatr Neurol 2018 02 13;79:45-52. Epub 2017 Nov 13.

Department of Epidemiology and Biostatistics and Pediatrics and Human Development, Michigan State University, East Lansing, Michigan.

Background: This study aims to determine the prevalence of neurodevelopmental impairments at age ten years among children born extremely preterm (less than 28 weeks gestational age) and to offer a framework for categorizing neurological limitations.

Methods: A multicenter, prospective cohort follow-up study recruited 889 ten-year-old children born from 2002 to 2004. We assessed prevalence of cognitive impairment, measured by intelligent quotient and tests of executive function, cerebral palsy (CP), autism spectrum disorder (ASD), and epilepsy singly and in combination. The three levels of impairment severity were: category I-no major neurodevelopmental impairment; category II-normal cognitive ability with CP, ASD, and/or epilepsy; and category III-children with cognitive impairment.

Results: A total 214 of 873 children (25%) had cognitive impairment, 93 of 849 children (11%) had CP, 61 of 857 children (7%) had ASD, and 66 of 888 children (7%) had epilepsy. Further, 19% of all children had one diagnosis, 10% had two diagnoses, and 3% had three diagnoses. Decreasing gestational age was associated with increasing number of impairments (P < 0.001). Half the children with cognitive impairment and one third of children with CP, ASD, or epilepsy had a single impairment. Six hundred one (68% [95% CI, 64.5%-70.7%]) children were in category I, 74 (8% [95% CI, 6.6%-10.3%]) were in category II, and 214 (24% [95% CI 21.7%-27.4%]) were in category III.

Conclusions: Three quarters of children had normal intellect at age ten years; nearly 70% were free of neurodevelopmental impairment. Forty percent of children with impairments had multiple diagnoses.
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http://dx.doi.org/10.1016/j.pediatrneurol.2017.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803305PMC
February 2018

Pretreatment behavior and subsequent medication effects in childhood absence epilepsy.

Neurology 2017 Oct 15;89(16):1698-1706. Epub 2017 Sep 15.

From Montefiore Medical Center (R.C.S., S.S., D.M., E.F.W.), Albert Einstein College of Medicine, Bronx, NY; George Washington University (A.C.), Washington, DC; Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine (P.C., C.L., T.A.G.), OH; The Children's Hospital of Philadelphia (D.D.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; National Institute of Neurological Disorders and Stroke (D.G.H.); and Henry M. Jackson Foundation for the Advancement of Military Medicine (F.H.), Bethesda, MD.

Objective: To characterize pretreatment behavioral problems and differential effects of initial therapy in children with childhood absence epilepsy (CAE).

Methods: The Child Behavior Checklist (CBCL) was administered at baseline, week 16-20, and month 12 visits of a randomized double-blind trial of ethosuximide, lamotrigine, and valproate. Total problems score was the primary outcome measure.

Results: A total of 382 participants at baseline, 310 participants at the week 16-20 visit, and 168 participants at the month 12 visit had CBCL data. At baseline, 8% (95% confidence interval [CI] 6%-11%) of children with CAE had elevated total problems scores (mean 52.9 ± 10.91). At week 16-20, participants taking valproic acid had significantly higher total problems (51.7 [98.3% CI 48.6-54.7]), externalizing problems (51.4 [98.3% CI 48.5-54.3]), attention problems (57.8 [98.3% CI 55.6-60.0]), and attention-deficit/hyperactivity problems (55.8 [98.3% CI 54.1-57.6]) scores compared to participants taking ethosuximide (46.5 [98.3% CI 43.4-49.6]; 45.8 [98.3% CI 42.9-48.7]; 54.6 [98.3% CI 52.4-56.9]; 53.0 [98.3% CI 51.3-54.8]). Lack of seizure freedom and elevated week 16-20 Conner Continuous Performance Test confidence index were associated with worse total problems scores. At month 12, participants taking valproic acid had significantly higher attention problems scores (57.9 [98.3% CI 55.6-60.3]) compared to participants taking ethosuximide (54.5 [95% CI 52.1-56.9]).

Conclusions: Pretreatment and ongoing behavioral problems exist in CAE. Valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine, further reinforcing ethosuximide as the preferred initial therapy for CAE.

Clinicaltrialsgov Identifier: NCT00088452.

Classification Of Evidence: This study provides Class II evidence that for children with CAE, valproic acid is associated with worse behavioral outcomes than ethosuximide or lamotrigine.
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http://dx.doi.org/10.1212/WNL.0000000000004514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5644466PMC
October 2017

Pretreatment seizure semiology in childhood absence epilepsy.

Neurology 2017 Aug 19;89(7):673-679. Epub 2017 Jul 19.

From the Children's Hospital of Philadelphia (S.K.K., D.D.), Perelman School of Medicine, University of Pennsylvania; Montefiore Medical Center (S.S., S.L.M.), Albert Einstein College of Medicine, Bronx, NY; Children's National Health System (A.C., J.C., F.H.), Washington, DC; National Institute of Neurological Disorders and Stroke (D.G.H.), Bethesda, MD; Comprehensive Epilepsy Center (C.L., P.C., T.A.G.), Division of Neurology, Cincinnati Children's Hospital Medical Center, OH; and Baylor College of Medicine (E.M.M.), Houston, TX.

Objective: To determine seizure semiology in children with newly diagnosed childhood absence epilepsy and to evaluate associations with short-term treatment outcomes.

Methods: For participants enrolled in a multicenter, randomized, double-blind, comparative-effectiveness trial, semiologic features of pretreatment seizures were analyzed as predictors of treatment outcome at the week 16 to 20 visit.

Results: Video of 1,932 electrographic absence seizures from 416 participants was evaluated. Median seizure duration was 10.2 seconds; median time between electrographic seizure onset and clinical manifestation onset was 1.5 seconds. For individual seizures and by participant, the most common semiology features were pause/stare (seizure 95.5%, participant 99.3%), motor automatisms (60.6%, 86.1%), and eye involvement (54.9%, 76.5%). The interrater agreement for motor automatisms and eye involvement was good (72%-84%). Variability of semiology features between seizures even within participants was high. Clustering analyses revealed 4 patterns (involving the presence/absence of eye involvement and motor automatisms superimposed on the nearly ubiquitous pause/stare). Most participants experienced more than one seizure cluster pattern. No individual semiologic feature was individually predictive of short-term outcome. Seizure freedom was half as likely in participants with one or more seizure having the pattern of eye involvement without motor automatisms than in participants without this pattern.

Conclusions: Almost all absence seizures are characterized by a pause in activity or staring, but rarely is this the only feature. Semiologic features tend to cluster, resulting in identifiable absence seizure subtypes with significant intraparticipant seizure phenomenologic heterogeneity. One seizure subtype, pause/stare and eye involvement but no motor automatisms, is specifically associated with a worse treatment outcome.
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http://dx.doi.org/10.1212/WNL.0000000000004226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562968PMC
August 2017

Cumulative Incidence of Seizures and Epilepsy in Ten-Year-Old Children Born Before 28 Weeks' Gestation.

Pediatr Neurol 2017 Aug 18;73:13-19. Epub 2017 May 18.

Department of Pediatrics and Neurology, Boston Medical Center, Boston, Massachusetts.

Objective: We evaluated the incidence of seizures and epilepsy in the first decade of life among children born extremely premature (less than 28 weeks' gestation).

Method: In a prospective, multicenter, observational study, 889 of 966 eligible children born in 2002 to 2004 were evaluated at two and ten years for neurological morbidity. Complementing questionnaire data to determine a history of seizures, all caregivers were interviewed retrospectively for postneonatal seizures using a validated seizure screen followed by a structured clinical interview by a pediatric epileptologist. A second pediatric epileptologist established an independent diagnosis based on recorded responses of the interview. A third epileptologist determined the final diagnosis when evaluators disagreed (3%). Life table survival methods were used to estimate seizure incidence through ten years.

Results: By age ten years, 12.2% (95% confidence interval: 9.8, 14.5) of children had experienced one or more seizures, 7.6% (95% confidence interval: 5.7, 9.5) had epilepsy, 3.2% had seizure with fever, and 1.3% had a single, unprovoked seizure. The seizure incidence increased with decreasing gestational age. In more than 75% of children with seizures, onset was after one year of age. Seizure incidence was comparable in both sexes. Two-thirds of those with epilepsy had other neurological disorders. One third of children with epilepsy were not recorded on the medical history questionnaire.

Significance: The incidence of epilepsy through age ten years among children born extremely premature is approximately 7- to 14-fold higher than the 0.5% to 1% lifetime incidence reported in the general pediatric population. Seizures in this population are under-recognized, and possibly underdiagnosed, by parents and providers.
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http://dx.doi.org/10.1016/j.pediatrneurol.2017.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524375PMC
August 2017

Developing standardized corticosteroid treatment for Duchenne muscular dystrophy.

Contemp Clin Trials 2017 07 24;58:34-39. Epub 2017 Apr 24.

University of Rochester Medical Center, United States.

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments.
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http://dx.doi.org/10.1016/j.cct.2017.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279424PMC
July 2017

Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring.

mSphere 2017 Jan-Feb;2(1). Epub 2017 Feb 22.

Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA.

Maternal infections during pregnancy are associated with risk of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Proposed pathogenetic mechanisms include fetal infection, placental inflammation, and maternal cytokines or antibodies that cross the placenta. The Autism Birth Cohort comprises mothers, fathers, and offspring recruited in Norway in 1999 to 2008. Through questionnaire screening, referrals, and linkages to a national patient registry, 442 mothers of children with ASD were identified, and 464 frequency-matched controls were selected. Immunoglobulin G (IgG) antibodies to , rubella virus, cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), and HSV-2 in plasma collected at midpregnancy and after delivery were measured by multiplexed immunoassays. High levels of HSV-2 IgG antibodies in maternal midpregnancy plasma were associated with increased risk of ASD in male offspring (an increase in HSV-2 IgG levels from 240 to 640 arbitrary units/ml was associated with an odds ratio of 2.07; 95% confidence interval, 1.06 to 4.06; = 0.03) when adjusted for parity and child's birth year. No association was found between ASD and the presence of IgG antibodies to , rubella virus, CMV, or HSV-1. Additional studies are needed to test for replicability of risk and specificity of the sex effect and to examine risk associated with other infections. The cause (or causes) of most cases of autism spectrum disorder is unknown. Evidence from epidemiological studies and work in animal models of neurodevelopmental disorders suggest that both genetic and environmental factors may be implicated. The latter include gestational infection and immune activation. In our cohort, high levels of antibodies to herpes simplex virus 2 at midpregnancy were associated with an elevated risk of autism spectrum disorder in male offspring. These findings provide support for the hypothesis that gestational infection may contribute to the pathogenesis of autism spectrum disorder and have the potential to drive new efforts to monitor women more closely for cryptic gestational infection and to implement suppressive therapy during pregnancy.
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http://dx.doi.org/10.1128/mSphere.00016-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322345PMC
February 2017

Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy.

N Engl J Med 2017 03;376(9):815-825

From the University of Texas Southwestern Medical Center, Dallas (B.M.C.), the University of Texas Medical Branch, Galveston (G.S.), and the University of Texas Health Science Center at Houston, McGovern Medical School-Children's Memorial Hermann Hospital, Houston (B.S.) - all in Texas; George Washington University Biostatistics Center, Washington, DC (E.A.T.); Northwestern University, Chicago (A.M.P.); the University of Utah Health Sciences Center, Salt Lake City (M.W.V.); Wayne State University, Detroit (Y.S.); the National Institute of Neurological Disorders and Stroke (D.G.H.) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.M.R.), Bethesda, MD; Columbia University, New York (R.J.W.); the University of North Carolina at Chapel Hill, Chapel Hill (J.M.T.); the University of Alabama at Birmingham, Birmingham (A.T.N.T.); Brown University, Providence, RI (D.J.R.); Ohio State University, Columbus (J.D.I.), and MetroHealth Medical Center-Case Western Reserve University, Cleveland (B.M.M.) - both in Ohio; Oregon Health and Science University, Portland (J.T.); University of Pittsburgh, Pittsburgh (S.N.C.); and the Medical University of South Carolina, Charleston (J.P.V.).

Background: Subclinical thyroid disease during pregnancy may be associated with adverse outcomes, including a lower-than-normal IQ in offspring. It is unknown whether levothyroxine treatment of women who are identified as having subclinical hypothyroidism or hypothyroxinemia during pregnancy improves cognitive function in their children.

Methods: We screened women with a singleton pregnancy before 20 weeks of gestation for subclinical hypothyroidism, defined as a thyrotropin level of 4.00 mU or more per liter and a normal free thyroxine (T) level (0.86 to 1.90 ng per deciliter [11 to 24 pmol per liter]), and for hypothyroxinemia, defined as a normal thyrotropin level (0.08 to 3.99 mU per liter) and a low free T level (<0.86 ng per deciliter). In separate trials for the two conditions, women were randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed monthly, and the levothyroxine dose was adjusted to attain a normal thyrotropin or free T level (depending on the trial), with sham adjustments for placebo. Children underwent annual developmental and behavioral testing for 5 years. The primary outcome was the IQ score at 5 years of age (or at 3 years of age if the 5-year examination was missing) or death at an age of less than 3 years.

Results: A total of 677 women with subclinical hypothyroidism underwent randomization at a mean of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was 97 (95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92 to 96) in the placebo group (P=0.71). In the hypothyroxinemia trial, the median IQ score was 94 (95% CI, 91 to 95) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo group (P=0.30). In each trial, IQ scores were missing for 4% of the children. There were no significant between-group differences in either trial in any other neurocognitive or pregnancy outcomes or in the incidence of adverse events, which was low in both groups.

Conclusions: Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20 weeks of gestation did not result in significantly better cognitive outcomes in children through 5 years of age than no treatment for those conditions. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00388297 .).
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http://dx.doi.org/10.1056/NEJMoa1606205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605129PMC
March 2017

Pharmacogenetics of antiepileptic drug efficacy in childhood absence epilepsy.

Ann Neurol 2017 Mar;81(3):444-453

University of Cincinnati College of Medicine, Cincinnati, OH.

Objective: To determine whether common polymorphisms in CACNA1G, CACNA1H, CACNA1I, and ABCB1 are associated with differential short-term seizure outcome in childhood absence epilepsy (CAE).

Methods: Four hundred forty-six CAE children in a randomized double-blind trial of ethosuximide, lamotrigine, and valproate had short-term seizure outcome determined. Associations between polymorphisms (minor allele frequency ≥ 15%) in 4 genes and seizure outcomes were assessed. In vitro electrophysiology on transfected CACNA1H channels determined impact of 1 variant on T-type calcium channel responsiveness to ethosuximide.

Results: Eighty percent (357 of 446) of subjects had informative short-term seizure status (242 seizure free, 115 not seizure free). In ethosuximide subjects, 2 polymorphisms (CACNA1H rs61734410/P640L, CACNA1I rs3747178) appeared more commonly among not-seizure-free participants (p = 0.011, odds ratio [OR] = 2.63, 95% confidence limits [CL] = 1.25-5.56; p = 0.026, OR = 2.38, 95% CL = 1.11-5.00). In lamotrigine subjects, 1 ABCB1 missense polymorphism (rs2032582/S893A; p = 0.015, OR = 2.22, 95% CL = 1.16-4.17) was more common in not-seizure-free participants, and 2 CACNA1H polymorphisms (rs2753326, rs2753325) were more common in seizure-free participants (p = 0.038, OR = 0.52, 95% CL = 0.28-0.96). In valproate subjects, no common polymorphisms were associated with seizure status. In vitro electrophysiological studies showed no effect of the P640L polymorphism on channel physiology in the absence of ethosuximide. Ethosuximide's effect on rate of decay of Ca 3.2 was significantly less for P640L channel compared to wild-type channel.

Interpretation: Four T-type calcium channel variants and 1 ABCB1 transporter variant were associated with differential drug response in CAE. The in vivo P640L variant's ethosuximide effect was confirmed by in vitro electrophysiological studies. This suggests that genetic variation plays a role in differential CAE drug response. Ann Neurol 2017;81:444-453.
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http://dx.doi.org/10.1002/ana.24886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171340PMC
March 2017

Targeting Environmental Neurodevelopmental Risks to Protect Children.

Pediatrics 2017 02;139(2)

Faculty of Health Sciences, Simon Fraser University, Vancouver, British Columbia, Canada.

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http://dx.doi.org/10.1542/peds.2016-2245DOI Listing
February 2017

Second monotherapy in childhood absence epilepsy.

Neurology 2017 Jan 16;88(2):182-190. Epub 2016 Dec 16.

From Children's National Health System (A.C.), Washington, DC; Montefiore Medical Center (S.S., D.M.), Albert Einstein College of Medicine, New York, NY; Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine (R.A., P.O.C., T.A.G.), OH; The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania (P.C.A., D.D.); and National Institute of Neurological Disorders and Stroke (D.G.H.), Bethesda, MD.

Objective: To determine optimal second monotherapy for children with childhood absence epilepsy (CAE) experiencing initial treatment failure.

Methods: Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16-20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits.

Results: A total of 208 children were enrolled, randomized, and received second therapy. At both week 16-20 visit and month 12 visit, ethosuximide's (63%, 57%) and valproic acid's (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine's (45%, 36%, p = 0.051 and p = 0.062). At both time points, ethosuximide and valproic acid had superior seizure control compared to lamotrigine (p < 0.0001). At both the week 16-20 and month 12 visits, attentional dysfunction was numerically more common with valproic acid than with ethosuximide or lamotrigine. For each medication, second monotherapy freedom from failure proportions demonstrated noninferiority to initial monotherapy freedom from failure proportions.

Conclusions: As second monotherapy, ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications.

Clinicaltrialsgov Identifier: NCT00088452.

Classification Of Evidence: This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with ethosuximide or valproic acid is superior to lamotrigine.
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http://dx.doi.org/10.1212/WNL.0000000000003480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224720PMC
January 2017

Extremely low gestational age and very low birthweight for gestational age are risk factors for autism spectrum disorder in a large cohort study of 10-year-old children born at 23-27 weeks' gestation.

Am J Obstet Gynecol 2017 Mar 12;216(3):304.e1-304.e16. Epub 2016 Nov 12.

Department of Pediatrics, Boston Medical Center, Boston, MA, USA.

Background: No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder separately among those with and without cognitive impairment.

Objective: We sought to identify perinatal factors associated with increased risk for autism spectrum disorder with and without intellectual disability (intelligence quotient <70) in children born extremely preterm.

Study Design: This prospective multicenter (14 institutions in 5 states) birth cohort study included children born at 23-27 weeks' gestation in 2002 through 2004 who were evaluated for autism spectrum disorder and intellectual disability at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical-vaginal "infection" refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4), or other/unspecified infection (n = 43; eg, chlamydia, trichomonas, or herpes). We do not know the extent to which infection per se was confirmed by microbial colonization. We use the terms "fetal growth restriction" and "small for gestational age" interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth restriction was defined as a birthweight Z-score for gestational age at delivery <-2 (ie, ≥2 SD below the median birthweight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into 4 groups based on whether or not they met rigorous diagnostic criteria for autism spectrum disorder and intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, autism spectrum disorder-/intellectual disability+, and autism spectrum disorder-/intellectual disability-). Temporally ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for autism spectrum disorder and/or intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, and autism spectrum disorder-/intellectual disability+).

Results: In all, 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for autism spectrum disorder; of these, 840 (98%) children were assessed for intellectual disability. Autism spectrum disorder+/intellectual disability- was diagnosed in 3.2% (27/840), autism spectrum disorder+/intellectual disability+ in 3.8% (32/840), and autism spectrum disorder-/intellectual disability+ in 8.5% (71/840). Maternal report of presumed cervical-vaginal infection during pregnancy was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.7; 95% confidence interval, 1.2-6.4). The lowest gestational age category (23-24 weeks) was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.3-6.6) and autism spectrum disorder+/intellectual disability- (odds ratio, 4.4; 95% confidence interval, 1.7-11). Severe fetal growth restriction was strongly associated with increased risk for autism spectrum disorder+/intellectual disability- (odds ratio, 9.9; 95% confidence interval, 3.3-30), whereas peripartum maternal fever was uniquely associated with increased risk of autism spectrum disorder-/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.2-6.7).

Conclusion: Our study confirms that low gestational age is associated with increased risk for autism spectrum disorder irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with autism spectrum disorder without intellectual disability. Maternal report of cervical-vaginal infection is associated with increased risk of autism spectrum disorder with intellectual disability, and peripartum maternal fever is associated with increased risk for intellectual disability without autism spectrum disorder.
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http://dx.doi.org/10.1016/j.ajog.2016.11.1009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5334372PMC
March 2017

Circulating Inflammatory-Associated Proteins in the First Month of Life and Cognitive Impairment at Age 10 Years in Children Born Extremely Preterm.

J Pediatr 2017 01 24;180:116-123.e1. Epub 2016 Oct 24.

Department of Epidemiology and Biostatistics and Pediatrics, Michigan State University, East Lansing, MI.

Objectives: To evaluate whether in children born extremely preterm, indicators of sustained systemic inflammation in the first month of life are associated with cognitive impairment at school age.

Study Design: A total of 873 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborn Study from 2002 to 2004 were evaluated at age 10 years. We analyzed the relationship between elevated blood concentrations of inflammation-associated proteins in the first 2 weeks ("early elevations"; n = 812) and the third and fourth week ("late elevations"; n = 532) of life with neurocognition.

Results: Early elevations of C-reactive protein, tumor necrosis factor-α, interleukin (IL)-8, intercellular adhesion molecule (ICAM)-1, and erythropoietin were associated with IQ values >2 SD below the expected mean (ORs: 2.0-2.3) and with moderate to severe cognitive impairment on a composite measure of IQ and executive function (ORs: 2.1-3.6). Additionally, severe cognitive impairment was associated with late protein elevations of C-reactive protein (OR: 4.0; 95% CI 1.5, 10), IL-8 (OR: 5.0; 1.9, 13), ICAM-1 (OR: 6.5; 2.6, 16), vascular endothelial growth factor-receptor 2 (OR: 3.2; 1.2, 8.3), and thyroid-stimulating hormone (OR: 3.1; 1.3, 7.3). Moderate cognitive impairment was most strongly associated with elevations of IL-8, ICAM-1, and vascular endothelial growth factor-receptor 2. When 4 or more inflammatory proteins were elevated early, the risk of having an IQ <70 and having overall impaired cognitive ability was more than doubled (ORs: 2.1-2.4); the presence of 4 or more inflammatory protein elevated late was strongly linked to adverse cognitive outcomes (ORs: 2.9-4.8).

Conclusions: Extremely preterm children who had sustained elevations of inflammation-related proteins in the first postnatal month are more likely than extremely preterm peers without such elevations to have cognitive impairment at 10 years.
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http://dx.doi.org/10.1016/j.jpeds.2016.09.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5183478PMC
January 2017

Cerebellar Hemorrhage in the Premature Infant-Time for a Balanced Approach.

J Pediatr 2016 11 12;178:9-10. Epub 2016 Aug 12.

Departments of Pediatrics and Neurology Yale School of Medicine New Haven, Connecticut.

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http://dx.doi.org/10.1016/j.jpeds.2016.07.036DOI Listing
November 2016

Report of a workshop on research gaps in the treatment of cerebral palsy.

Neurology 2016 Sep 24;87(12):1293-8. Epub 2016 Aug 24.

From the Office of the Clinical Director (C.L.) and Office of Clinical Research (D.H.), National Institute of Neurological Disorders and Stroke, NIH, Bethesda; Functional and Applied Biomechanics Section (D.D.), Clinical Center, NIH, Bethesda, MD; Cerebral Palsy Research Network (P.G.), Woodinville, WA; and Departments of Neurology, Neuroscience, and Pediatrics (J.W.M.), University of Rochester, NY.

Cerebral palsy (CP) is heterogeneous in etiology and manifestations, making research into relevant therapies difficult and limiting the generalizability of the results. We report here on the NIH CP symposium, where stakeholders from academic, clinical, regulatory, and advocacy backgrounds discussed the major challenges and needs for moving forward with clinical research in CP, and outlined priorities and action items. New information is constantly generated through research into pathogenesis and etiology. Clinical research and new therapeutic approaches need to keep pace, through large data registry integration and new research designs. Development of standardized data collection, increasing academic focus on CP research, and iterative approaches to treatment throughout the patients' lives, have all been identified as areas of focus. The workshop identified critical gaps and areas of focus to increase the evidence base for therapeutic approaches to determine which treatments work best for which patients in the near future. These include consolidation and optimization of databases and registries, updates to the research methodology, and better integration of resources and stakeholders.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035982PMC
http://dx.doi.org/10.1212/WNL.0000000000003116DOI Listing
September 2016

Prevalence and associated features of autism spectrum disorder in extremely low gestational age newborns at age 10 years.

Autism Res 2017 Feb 25;10(2):224-232. Epub 2016 May 25.

Department of Pediatrics, Boston Medical Center, Boston, Massachusetts.

We sought to estimate the prevalence of autism spectrum disorder (ASD) in children born extremely preterm relative to the U.S. population risk of 1.5% [CDC, 2014] using the best-available diagnostic procedures and minimizing confounding with other neurodevelopmental impairments. Eight hundred and eighty nine of 966 (92%) 10-year-old children from the Extremely Low Gestational Age Newborn birth cohort, delivered at 23-27 weeks gestation in 2002-2004, participated. Children meeting ASD screening criteria on the Social Communication Questionnaire were evaluated with the Autism Diagnostic Interview-Revised (ADI-R). Those meeting ADI-R criteria were assessed with the Autism Diagnostic Observation Schedule-2 (ADOS-2). A positive ADOS-2 score was the criterion for ASD. Twenty-six participants were not assessed for ASD because of severe sensory or motor impairment. In the remaining sample, 61 children met criteria for ASD, resulting in a prevalence of 7.1% (95% CI = 5.5-9.0). ASD risk decreased with increasing gestational age, from 15.0% (95% CI = 10.0-21.2) for 23-24 weeks, 6.5% (95% CI = 4.2-9.4) for 25-26 weeks, to 3.4% (95% CI = 1.6-6.1) for 27 weeks gestational age, and this association was independent of IQ. Among children with ASD, 40% had intellectual disability. The male-to-female ratio of children with ASD was 2.1:1 (95% CI = 1.2:1-3.5:1), lower than in the general population (4:1). ASD prevalence in the ELGAN cohort was four times higher than in the general population, and was strongly associated with gestational age, underscoring the need for enhanced ASD screening of children born preterm, and suggesting that some risk factors associated with preterm birth may also play a role in the etiology of autism. Autism Res 2017, 10: 224-232. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/aur.1644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123971PMC
February 2017

What we learned about the role of antenatal magnesium sulfate for the prevention of cerebral palsy.

Semin Perinatol 2016 08 23;40(5):303-6. Epub 2016 Apr 23.

Department of Neurological Sciences and Pediatrics, University of Vermont HSRF 426, 149 Beaumont Avenue, Burlington, VT 05405.

Based on the convincing case control study of Nelson and Grether which suggested that the administration of magnesium sulfate to mothers prior to early preterm birth might protect their offspring from cerebral palsy, and a pilot study by John Hauth et al. at the University of Alabama at Birmingham, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network, with co-funding from the National Institute of Neurologic Disorders and Stroke embarked on the Beneficial Effects of Antenatal Magnesium (BEAM) Trial in 1997.
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http://dx.doi.org/10.1053/j.semperi.2016.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314306PMC
August 2016

Neurocognitive and Academic Outcomes at Age 10 Years of Extremely Preterm Newborns.

Pediatrics 2016 Apr 22;137(4). Epub 2016 Mar 22.

Department of Pediatrics, Boston Medical Center, Boston, Massachusetts.

Background And Objective: Despite reductions in mortality and morbidity among children born extremely preterm, they remain at high risk of neurocognitive deficits, with up to 40% having significant cognitive deficits at school age. We assessed the rate of neurocognitive impairment in a contemporary US cohort of 873 children aged 10 years who were born <28 weeks' gestation.

Methods: The families of 889 of 966 (92%) children enrolled from 2002 to 2004 at 14 sites in 5 states returned at age 10 years for a comprehensive assessment of IQ, language, attention, executive function, processing speed, visual perception, visual-motor function, and academic achievement.

Results: A total of 873 children were assessed with well-validated tests of cognitive and academic function. Distributions of test scores were consistently and markedly shifted below normative expectation, with one-third to two-thirds of children performing >1 SD below age expectation. The most extreme downward shifts were on measures of executive control and processing speed. Multivariate analyses, adjusted for socioeconomic status, growth restriction, and other potential confounders, revealed that the risk of poor outcome was highest at the lowest gestational age across all 18 measures.

Conclusions: More than half of our extremely preterm cohort exhibited moderate or severe neurocognitive deficits at age 10 years, with the most extensive impairments found among those born at the lowest gestational age. Children born extremely preterm continue to be at significant risk of persistent impairments in neurocognitive function and academic achievement, underscoring the need for monitoring and remediating such outcomes beginning in early childhood.
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http://dx.doi.org/10.1542/peds.2015-4343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811321PMC
April 2016

Girls and Boys Born before 28 Weeks Gestation: Risks of Cognitive, Behavioral, and Neurologic Outcomes at Age 10 Years.

J Pediatr 2016 Jun 19;173:69-75.e1. Epub 2016 Mar 19.

Department of Neurology, Harvard Medical School, Boston, MA; Department of Neurology, Neuroepidemiology Unit, Boston Children's Hospital, Boston, MA.

Objectives: To compare the prevalence of cognitive, neurologic, and behavioral outcomes at 10 years of age in 428 girls and 446 boys who were born extremely preterm.

Study Design: A total of 889 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborns Study from 2002-2004 were evaluated at 10 years of age. Children underwent a neuropsychological battery and testing for autism spectrum disorder (ASD), and parents reported on their child's behavior, development, and seizures.

Results: Of the children, 28% of boys and 21% of girls exhibited moderate to severe impairment on summary measures of cognitive abilities. Boys had a higher prevalence of impairment than girls in nearly all measures of cognition, were more than twice as likely to have microcephaly (15% in boys, 8% in girls), and require more often assistive devices to ambulate (6% in boys, 4% in girls). In contrast, boys and girls had comparable risk for a history of seizure (identified in 10% of the cohort) or epilepsy (identified in 7% of the cohort). The boy-to-girl ratio of ASD (9% in boys, 5% in girls) was lower than expected compared with the overall US autism population.

Conclusions: In this contemporary cohort of children born extremely premature and evaluated at school age, boys had higher prevalence of cognitive, neurologic, and behavioral deficits than girls. The ratio of boys to girls among those with ASD deserves further study as does the perinatal environmental-genetic interactions that might contribute to male preponderance of deficits in this high-risk sample.
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http://dx.doi.org/10.1016/j.jpeds.2016.02.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884461PMC
June 2016