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1.  Results from a phase 1 study of nusinersen (ISIS-SMNRx) in children with spinal muscular atrophy 
Neurology  2016;86(10):890-897.
Objective:
To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA).
Methods:
Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2–14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6–10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory.
Results:
A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4–6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9–14 months postdose (5.8 points; p = 0.008) during the extension study.
Conclusions:
Results from this study support continued development of nusinersen for treatment of SMA.
Classification of evidence:
This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.
doi:10.1212/WNL.0000000000002445
PMCID: PMC4782111  PMID: 26865511
2.  Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study 
Abstract
Objective
This study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA).
Methods
This prospective, multi‐center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits.
Results
Enrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items (TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP‐INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude (CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography (EIM) high‐frequency reactance slope (Ohms/MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron (SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts.
Interpretation
By the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit.
doi:10.1002/acn3.283
PMCID: PMC4748311  PMID: 26900585
3.  Neurobehavioral and Developmental Traiectories Associated with Level of Prenatal Cocaine Exposure 
Introduction
In experimental models, prenatal cocaine exposure has been found to perturb GABA and dopamine development. Clinically, abnormalities in tone, posture and state regulation are noted in early infancy but the evolution of these findings over time is not well described. The current study assesses the longitudinal effects of prenatal cocaine exposure in dose-dependent fashion on developmental & behavioral and neurological trajectories over the first 2 years of life.
Methods
Three hundred and eighty infants, 113 cocaine-exposed, were enrolled at birth from an urban hospital from 2000 to 2004. Exposure was determined by maternal interview, segmental hair analyses (RIAH™) in all, and meconium and urine in a subset. Developmental, behavioral and neurological assessments were carried out blind to drug exposure at 6, 12 and 24 months of age in the 306 children who returned in follow-up. Mixed-effects linear modeling (developmental growth curve) assessed change in outcome over time.
Results
The mental developmental growth curve showed a negative slope (2.2 points) in adjusted analyses among cocaine-exposed children over the first 2 years of life. (p=.04), while the slope of the motor development growth curve did not. Adjusting for microcephaly at 6 months diminished the strength of the association between cocaine exposure and mental developmental growth curve (effect modification). Cocaine exposure was marginally associated with behavioral outcomes in adjusted analyses. Total Behavior scores and Orientation/Engagement scores improved with age. At 1 year of age, prenatal cocaine exposure was significantly associated with lower motor development scores. High rates of hypertonia (global and diparesis) identified at the 6-month visit dropped dramatically in the first 2 years of life: cocaine-exposed children showed a more rapid rate of resolution of hypertonia than unexposed children, with hypertonia improving 2.2 times faster among those with heavy cocaine exposure.
Conclusion
We found differences in mental performance over the first 2 years of life associated with prenatal cocaine exposure that was mediated by microcephaly implying that cocaine exerts a sustained teratogenic effect on brain development. Early neurological (hypertonia) and behavioral findings associated with prenatal cocaine exposure improved over time. Hypertonia did not predict long-term development impairments. Conceivably, the transient nature of neurobehavioral manifestations reflects postnatally a tendency towards homeostasis of cocaine-related embryopathic perturbations of GABA and dopaminergic systems.
doi:10.13188/2332-3469.1000015
PMCID: PMC4318507  PMID: 25664330
Perinatal; Cocaine exposure; Behavior; Drug use; Hypertonia; Neurologic; Child development
4.  Prenatal Cocaine Exposures and Dose-Related Cocaine Effects on Infant Tone and Behavior 
Neurotoxicology and teratology  2006;29(3):323-330.
Background
In experimental models, prenatal cocaine exposure has been found to perturb monoaminergic development. In humans, numerous studies have sought clinical correlates, but few have focused on dose-related effects, especially as regards neurologic function beyond the neonatal period.
Objective
To assess whether prenatal cocaine exposure has adverse effects on infant neurologic, developmental and behavioral outcomes and whether any effects are dose-dependent.
Design/Methods
Infants (398) were enrolled at birth from an urban hospital. Drug exposure was ascertained with biomarkers in hair (n=395), urine (n=170) and meconium (n=109). Children were followed prospectively and 286 (72%) were evaluated blind to drug exposure at 6 months of age with the Bayley scales, Fagan Scale of Infant Intelligence and a standardized neurological examination.
Results
Certain neurological findings increased significantly by the amount of cocaine detected in maternal hair, e.g. abnormality of tone, as indicated by extensor posture was detected among 28% of cocaine-unexposed infants, 43% of infants exposed to lower and 48% exposed to higher cocaine levels in maternal hair (p<0.009). Persistent fisting increased in a similar dose-dependent manner. These associations persisted in adjusted analyses. Prenatal cocaine exposure was not associated with developmental scores (mental, motor or novelty preference) but was associated with lower orientation scores in adjusted analyses.
Conclusions
At 6 months of age, prenatal cocaine exposure was associated with abnormalities of tone and posture and with lower orientation scores. Perturbations in monoaminergic systems by cocaine exposure during fetal development may explain the observed neurological and behavioral symptoms. Whether such findings in infancy increase the risk of later neurobehavioral problems requires further study.
doi:10.1016/j.ntt.2006.12.002
PMCID: PMC4307783  PMID: 17234383
perinatal; cocaine exposure; drug use; hypertonia; child development
5.  Maternal Periodontitis Treatment and Child Neurodevelopment at 24 to 28 Months of Age 
Pediatrics  2011;127(5):e1212-e1220.
BACKGROUND:
Some maternal infections are associated with impaired infant cognitive and motor performance. Periodontitis results in frequent bacteremia and elevated serum inflammatory mediators.
OBJECTIVE:
The purpose of this study was to determine if periodontitis treatment in pregnant women affects infant cognitive, motor, or language development.
METHODS:
Children born to women who had participated in a previous trial were assessed between 24 and 28 months of age by using the Bayley Scales of Infant and Toddler Development (Third Edition) and the Preschool Language Scale (Fourth Edition). Information about the pregnancy, neonatal period, and home environment was obtained through chart abstractions, laboratory test results, and questionnaires. We compared infants born to women treated for periodontitis before 21 weeks' gestation (treatment group) or after delivery (controls). In unadjusted and adjusted analyses, associations between change in maternal periodontal condition during pregnancy and neurodevelopment scores were tested by using Student's t tests and linear regression.
RESULTS:
A total of 411 of 791 eligible mother/caregiver-child pairs participated. Thirty-seven participating children (9.0%) were born at <37 weeks' gestation. Infants in the treatment and control groups did not differ significantly for adjusted mean cognitive (90.7 vs 91.4), motor (96.8 vs 97.2), or language (92.2 vs 92.1) scores (all P > .5). Results were similar in adjusted analyses. Children of women who experienced greater improvements in periodontal health had significantly higher motor and cognitive scores (P = .01 and .02, respectively), although the effect was small (∼1-point increase for each SD increase in the periodontal measure).
CONCLUSION:
Nonsurgical periodontitis treatment in pregnant women was not associated with cognitive, motor, or language development in these study children.
doi:10.1542/peds.2010-3129
PMCID: PMC3081189  PMID: 21482606
child neurodevelopment; periodontitis; pregnancy; treatment

Results 1-5 (5)