Neonatal opioid exposure:public health crisis and novel neuroinflammatory disease

Substance use,specifically the use of prescription and non-prescription opioids among pregnant women,is a major public health issue and chief contributor to the opioid crisis.The prevalence of Neonatal Opioid Withdrawal Syndrome has risen 5-fold in the past decade,and is a well-recognized consequence of perinatal opioid exposure.By contrast,the long-term damage to the developing brain from opioid medications is just beginning to be recognized as a serious concern.Published data suggest that opioid exposure commencing in utero negatively affects the maturation of the neural-immune system,and trajectory of central nervous system development.Methadone induces peripheral immune hyper-reactivity,lasting structural and microstructural brain injury,and significant deficits in executive function and cognitive control in adult animals following in utero exposure.Thus,to address the cascading public health crisis stemming from the multitude of infants with in utero opioid exposure who will grow up with altered neurodevelopmental trajectories,rigorous preclinical,mechanistic studies are required.Such studies will define the long-term sequelae of prenatal opioid exposure in an effort to develop appropriate and targeted interventions.Specifically,the development of novel fluid,neuroimaging and biobehavioral biomarkers will be the most useful to aid in early identification and treatment of opioid exposed infants with the greatest risk of poor clinical outcomes.These studies will be essential to understand how in utero insults determine brain structure and function in adulthood,and what targeted interventions will be required to improve longterm outcomes in the countless children being born exposed to opioids each year.

Potential for treatment of severe autism in tuberous sclerosis complex

The Food and Drug Administration(FDA) has approved two mechanismbased treatments for tuberous sclero-sis complex(TSC)-everolimus and vigabatrin. However, these treatments have not been systematically studied in individuals with TSC and severe autism. The aim of this review is to identify the clinical features of severe autism in TSC, applicable preclinical models, and potential barriers that may warrant strategic planning in the design phase of clinical trial development. A comprehensive search strategy was formed and searched across Pub Med, Embase and SCOPUS from their inception to 2/21/12, 3/16/12, and 3/12/12 respectively. After the final search date, relevant, updated articles were selected from Pub Med abstracts generated electronically and emailed daily from Pub Med. The references of selected articles were searched, and relevant articles were selected. A search of clinicaltrials.gov was completed using the search term "TSC" and "tuberous sclerosis complex". Autism has been reported in as many as 60% of individuals with TSC; however, review of the literature revealed few data to support clear classification of the severity of autism in TSC. Variability was identified in the diagnostic approach, assessment of cognition, and functional outcome among the reviewed studies and case reports. Objective outcome measures were not used in many early studies; however, diffusion tensor imaging of white matter, neurophysiologic variability in infantile spasms, and cortical tuber subcategories were examined in recent studies and may be useful for objective classification of TSC in future studies. Mechanism-based treatments for TSC are currently available. However, this literature review revealed two potential barriers to successful design and implementation of clinical trials in individuals with severe autism-an unclear definition of the population and lack of validated outcome measures. Recent studies of objective outcome measures in TSC and further study of applicable preclinical models present an opportunity to overcome these barriers.